# Liver X receptors and the hallmarks of aging: From molecular mechanisms to therapeutic opportunities

Marc Poirot, Julio Buñay, Silia Ayadi, Sandrine Silvente-Poirot, Philippe de Medina

► To cite this version:

Marc Poirot, Julio Buñay, Silia Ayadi, Sandrine Silvente-Poirot, Philippe de Medina. Liver X receptors and the hallmarks of aging: From molecular mechanisms to therapeutic opportunities. Ageing Research Reviews - ARR, 2026, 114, pp.102967. 10.1016/j.arr.2025.102967. inserm-05394944

HAL Id: inserm-05394944

https://inserm.hal.science/inserm-05394944v1

Submitted on 3 Dec 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
<figure><img src="image_2.png" /></figure>

Review article

# Liver X receptors and the hallmarks of aging: From molecular mechanisms to therapeutic opportunities

Marc Poirot*, Julio Buñay, Silia Ayadi, Sandrine Silvente-Poirot, Philippe de Medina

<figure><img src="image_3.png" /></figure>

Team INOV, Cancer Research Center of Toulouse, Inserm, CNRS, University of Toulouse, Toulouse, France

ARTICLE INFO

Keywords:

Aging

Liver X receptors

Oxysterols

Hallmarks of aging

Age-related diseases

A B S T R A C T

Aging is the primary risk factor for cardiovascular disease, cancer, neurodegeneration, and other chronic disorders. Therefore, targeting the hallmarks of aging has emerged as a promising strategy to extend healthspan. Liver X receptors (LXRs) are ligand-dependent nuclear receptors that are activated by specific oxysterols and cholesterol derivatives. They are traditionally known as key regulators of cholesterol homeostasis. However, recent evidence reveals that LXRs also influence autophagy, mitochondrial function, epigenetics, senescence, stem cell dynamics, and intercellular communication. This positions LXRs at the crossroads of multiple hallmarks of aging. This review synthesizes current knowledge on endogenous and synthetic LXR ligands, their transcriptional mechanisms, and their effects on the aforementioned hallmarks and age-related pathophysiology. The clinical development of pan-LXR agonists for atherosclerosis has been hindered by side effects, notably hepatic steatosis. Emerging strategies, including LXRβ-selective ligands, selective LXR modulators (SLiMs), and biased agonists such as dendrogenin A, offer ways to separate the protective vascular, metabolic, and neuroprotective effects from adverse outcomes. Additionally, we explore how LXR signaling intersects with the hallmarks of aging and how it can be leveraged to intervene in atherosclerosis, diabetes, cancer, osteoporosis, age-related macular degeneration, and neurodegenerative diseases. Positioning LXRs within the geroscience framework suggests that LXRs may serve as pharmacological hubs to delay aging and its comorbidities. Future work should prioritize isoform- and tissue-selective approaches, metabolite-inspired ligand design, and integration with the hallmarks of aging to unlock the full therapeutic potential of LXRs.

# 1. Introduction

The World Health Organization (WHO) identifies cardiovascular disease and cancer as the leading causes of death globally (Collaborators, 2018; ReFaey et al., 2021). Yet modeling studies indicate that eliminating mortality from these diseases would yield only modest gains in human lifespan (Mackenbach et al., 1999). This underscores a central paradox in biomedicine: targeting individual pathologies is insufficient to meaningfully extend life expectancy or healthspan, because new fatal conditions inevitably emerge.

Aging itself is now recognized as the major risk factor for most life-limiting disorders, including cancer, cardiovascular disease, and neurodegeneration (Franceschi et al., 2018a). Experimental evidence across organisms, from yeast to mammals, demonstrates that aging is a malleable biological process that can be delayed through dietary, genetic, and pharmacological interventions (Barardo et al., 2017). This realization has fueled the rise of geroscience, which seeks to target

fundamental mechanisms of aging to prevent or postpone multiple chronic diseases simultaneously (Rolland et al., 2023).

Conceptual advances have converged on the “hallmarks of aging,” a framework that unifies the interconnected processes driving organismal decline (Biga et al., 2025; Lopez-Otin et al., 2023a; López-Otin et al., 2013). Twelve hallmarks are currently recognized: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, impaired macroautophagy, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. Additional contributors, including stress response dysregulation and metabolic perturbations, further shape the aging trajectory (Kennedy et al., 2014).

Pharmacological approaches under clinical evaluation primarily target nutrient- and energy-sensing pathways such as mTOR, AMPK, sirtuins, and IGF-1 signaling, often with compounds including rapamycin, metformin, NAD+ precursors, and senolytics (Guarente et al., 2024). Despite these advances, the identification of new druggable targets

<footnote>* Corresponding authors.</footnote>

<footnote>E-mail addresses: marc.poirot@inserm.fr (M. Poirot), philippe.de-medina@inserm.fr (P. de Medina).</footnote>
remains essential.

In this context, we have proposed that the *oxysterome*, the structurally diverse family of oxygenated cholesterol derivatives, contains physiological regulators of aging (de Medina et al., 2022). Several oxysterols (OS), including side-chain OS, sulfated OS, bile acids, and B-ring OS such as dendrogenin A (DDA), act as endogenous ligands for liver X receptors (LXRs) (El-Gendy et al., 2018; Janowski et al., 1999; Komati et al., 2017; Poirot and Silvente-Poirot, 2018; Viennois et al., 2012). LXRs, expressed as LXRα (NR1H3) and LXRβ (NR1H2), belong to the nuclear receptor superfamily and function as ligand-activated transcription factors. While best known for their central role in cholesterol homeostasis, LXRs also regulate fertility, inflammation, energy metabolism, skin homeostasis, cancer, and neurogenesis (Chang et al., 2008; Korach-Andre et al., 2011; Sacchetti et al., 2009; Silvente-Poirot et al., 2018a; Volle et al., 2007; Zelcer and Tontonoz, 2006).

These broad regulatory capacities place LXRs at the crossroads of metabolic, inflammatory, and regenerative pathways, making them attractive but challenging drug targets. In this review, we integrate LXR biology within the hallmarks of aging framework, highlighting how LXR signaling may be leveraged to extend healthspan and delay age-related disease.

## 2. Mechanisms of LXR-driven gene regulation and ligand-dependent modulation of gene expression

LXRs act as ligand-dependent transcription factors whose modular architecture enables sterol sensing and orchestration of diverse transcriptional programs. Like other nuclear receptors, they comprise an N-terminal activation function-1 (AF-1) domain supporting ligand-independent activity, a highly conserved DNA-binding domain (DBD) with two zinc fingers, a hinge bearing the nuclear localization sequence, a ligand-binding domain (LBD) that mediates ligand recognition and dimerization, and a C-terminal activation function-2 (AF-2) that recruits coactivators upon ligand binding (Fig. 1A) (Weikum et al., 2018). LXRs form obligate heterodimers with Retinoid X Receptors (RXRs) and recognize LXR response elements (LXREs), typically DR4 motifs (direct repeats of 5'-G/AGGTCA-3' separated by four nucleotides) (Willy et al., 1995; Fig. 1A-C). Through these interactions, LXRs regulate programs

that control cholesterol homeostasis, lipogenesis, endocrine signaling, inflammation, cellular differentiation, autophagy-lysosome function, and secretion (Burris et al., 2023; Fessler, 2018; Guillemot-Legris and Muccioli, 2021; Record et al., 2022; Segala et al., 2017; Segala et al., 2013; Serhan et al., 2020).

Given this breadth, LXRs are prominent pharmacological targets across atherosclerosis, cancer, and neurodegenerative disease (Calkin and Tontonoz, 2010; Fessler, 2018; Komati et al., 2017; Lin and Gustafsson, 2015; Wang and Tontonoz, 2018; Zhang et al., 2023a). This section first outlines core principles of LXR transcriptional control, then surveys endogenous and synthetic ligands that drive subtype- and tissue-specific outcomes.

### 2.1. LXRs and gene transcription

#### 2.1.1. Genes and biological processes regulated by LXRs

LXRs were first recognized as master regulators of cholesterol homeostasis. Canonical targets include transporters and apolipoproteins that drive reverse cholesterol transport (RCT) ABCA1, ABCG1, APOE as well as factors governing lipoprotein uptake (IDOL), remodeling (CETP, PLTP), intracellular sterol transport (NPC1, NPC2), intestinal absorption (ABCG5, ABCG8, NPC1L1), and sterol sulfation (SULT2A1, SULT2B1b, SULT1E1) (Cook and Leyh, 2023; Hong and Tontonoz, 2014; Segala et al., 2017); Fig. 2). LXR activation also induces a lipogenic program via SREBP1c and downstream enzymes (ACC, FASN, SCD1) (Repa et al., 2000; Schultz and Sinclair, 2016). Beyond neutral lipid synthesis, LXRs remodel phospholipid pools and mitigate endoplasmic reticulum (ER) stress by upregulating LPCAT3 and PCYT2 (Rong et al., 2013; Zhu and Bakovic, 2008).

In innate immunity, LXRs restrain inflammatory tone by repressing COX2, iNOS, IL-6, IL-1β, TNFα, IL-12, and RANTES, while inducing pro-resolving mediators (Arginase II, IL-10, MERTK, 15-LOX, TGFβ) (Bilotta et al., 2019; Joseph et al., 2003; Marathe et al., 2006; Ohno et al., 2024). Metabolic control extends to glucose handling: LXRs regulate uptake (GLUT1, GLUT4), glycolysis (HK2, PFKFB2, LDHA), and gluconeogenesis (G6Pase, PEPCK) (Laffitte et al., 2003; Steffensen and Gustafsson, 2004).

LXRs also influence lineage decisions and tissue homeostasis. They

<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /><figcaption>**Fig. 1.** A) Structural organization of the liver X receptor. The general domain structure of nuclear receptors is composed of an A/B domain that carries the activation function-1 (AF-1) region, a DNA-binding domain (DBD), a hinge region H, and a ligand-binding domain (LBD) that carries the activation function-2 (AF-2) region. B) Crystal structure of the complex RXRα/LXRβ complexed with their respective cognate ligands 9 cis retinoic acid and GW3965 and a LXRE (PDB: 4NQA). RXRα LBD (red ribbon), cis-retinoic acid (light brown atom-colored sticks), N-CoA2 coactivator peptide (grey ribbon), LXRβ LBD (green ribbon) GW3965 (blue atom-colored sticks), RXRα DBD (red ribbon), LXRβ DBD (green ribbon), DR-4 (brown DNA). C) Schematic representation of LXR regulating transcription. LXR heterodimerizes with RXR and binds to the liver-X-receptor element (LXRE), which is made of a direct repeat of a hexanucleotide separated by four nucleotides (DR4).</figcaption></figure>
<figure><img src="image_6.png" /><figcaption>**Fig. 2.** LXRs regulation of biological functions. Protein symbols are used throughout the figure; gene names are given in brackets when different from the protein. ABCA1: ATP-binding cassette transporter A1; ABCA12: ATP-binding cassette transporter A12; ABCG1: ATP-binding cassette transporter G1; ABCG5: ATP-binding cassette transporter G5; ABCG8: ATP-binding cassette transporter G8; ACC (ACACA): Acetyl-CoA carboxylase; ACSL3: Long-chain acyl-CoA synthetase 3; ARGII: Arginase II; ATG3: Ubiquitin-like modifier-activating enzyme ATG3; ATG7: Ubiquitin-like modifier-activating enzyme ATG7; BMP: Bis(monoacylglycerol)phosphate; CD63: CD63 antigen; CETP: Cholesteryl ester transfer protein; COX2 (PTGS2): Cyclooxygenase-2; CYP11A1: Cytochrome P450 family 11 subfamily A member 1; DAT (SLC6A3): Dopamine transporter; ELOVL5: Elongation of very long-chain fatty acids protein 5; FASN: Fatty acid synthase; Filaggrin (FLG): Filaggrin; GLUT1 (SLC2A1): Glucose transporter type 1; GLUT4 (SLC2A4): Glucose transporter type 4; G6Pase (G6PC): Glucose-6-phosphatase; HK2: Hexokinase 2; HSD3B1: 3β-hydroxysteroid dehydrogenase type 1; IL-1β (IL1B): Interleukin-1β; IL-6 (IL6): Interleukin-6; IL-10 (IL10): Interleukin-10; IL-12 (IL12): Interleukin-12; iNOS (NOS2): Inducible nitric oxide synthase; Involucrin (IVL): Involucrin; LC3 (MAP1LC3B): Microtubule-associated protein 1 light chain 3; Loricrin (LOR): Loricrin; LPCAT3: Lysophosphatidylcholine acyltransferase 3; MAP2: Microtubule-associated protein 2; MDR1 (ABCB1): Multidrug Resistance 1; MelanA (MLANA): Melanoma antigen recognized by T cells 1; Nor1 (NR4A3): Nuclear receptor subfamily 4 group A member 3; Nur77 (NR4A1): Nuclear receptor subfamily 4 group A member 1; PCYT2: Ethanolamine-phosphate cytidylyltransferase; PEPCK (PCK1): Phosphoenolpyruvate carboxykinase; PLTP: Phospholipid transfer protein; Rab27a (RAB27A): Ras-related protein Rab-27a; RANTES (CCL5): C-C motif chemokine ligand 5; SCD1: Stearoyl-CoA desaturase 1; SMPDL3A: Sphingomyelin Phosphodiesterase Acid-Like 3 A; SREBP1c (SREBF1): Sterol regulatory element-binding protein 1c; StAR (STAR): Steroidogenic acute regulatory protein; SULT2E1: Sulfotransferase 2E1; SULT2A1: Sulfotransferase 2A1; TFEB: Transcription factor EB; TH: Tyrosine hydroxylase; TRP2 (TYRP2): Tyrosinase-related protein 2; Tuj1 (TUBB3): Class III β-tubulin; TNFα (TNF): Tumor necrosis factor alpha; TYR: Tyrosinase.</figcaption></figure>

promote dopaminergic neuronal markers (Tuj1, MAP2, TH1, DAT) (Singh et al., 2021), drive keratinocyte terminal differentiation (filaggrin, involucrin, loricrin, ABCA12) (Chang et al., 2008; Schmuth et al., 2008), and modulate melanocyte programs (tyrosinase, TRP2, MelanA). Endocrine regulation encompasses both steroidogenesis (STAR, CYP11A1, HSD3B1) and steroid inactivation via sulfation (SULT1E1, SULT2A1) (Cummins et al., 2006; Dallel et al., 2018; Gong et al., 2007; Nilsson et al., 2007; Ou et al., 2014). Finally, LXRs couple to cellular quality control and secretion by inducing lysosome-autophagy genes

(Nur77, Nor1, TFEB, LC3) and by enhancing exosome biogenesis/trafficking (CD63, LC3-II, RAB27A) alongside bis(monoacylglycerol)phosphate (BMP) production (de Medina et al., 2023a; Record et al., 2022; Segala et al., 2017).

Collectively, LXRs coordinate programs spanning lipid metabolism, inflammation, glucose balance, differentiation, endocrine signaling, autophagy-lysosome function, and vesicle-mediated communication breadth that underpins their therapeutic appeal (Lin and Gustafsson, 2015; Silvente-Poirot et al., 2018a; Silvente-Poirot et al., 2018b;
Viennois et al., 2012; Zhang et al., 2023a).

### 2.1.2. Mechanism of LXR-dependent regulation of gene transcription

The classical model posits that LXR/RXR heterodimers occupy LXRs (typically DR4). In the absence of ligand, association with NCoR/HDAC complexes enforces repression; agonist engagement remodels the LBD, expels corepressors, and recruits coactivators to drive transcription (Pehkonen et al., 2012; Wagner et al., 2003; Willy et al., 1995). This switch explains archetypal control of ABCA1 and SREBF1 (Jakobsson et al., 2009).

Genome-wide studies reveal a broader logic. Ligands recruit LXRs de novo to many loci, with occupancy extending beyond DR4 to DR1 and half-sites, expanding the cistrome (Boergesen et al., 2012; Fessler, 2018; Penvose et al., 2019). In parallel, LXRs impose negative control through trans-repression ligand-dependent SUMOylation stabilizes NCoR/SMRT at NF-κB and AP-1 targets and cis-repression, which reduces enhancer accessibility at inflammatory loci and selected negative promoters in cholesterol biosynthesis while simultaneously activating efflux programs (Ghisletti et al., 2007; Thomas et al., 2018).

Functionally, this combinatorial toolkit canonical activation, ligand-induced chromatin engagement, and dual repression modes explains how LXRs can simultaneously upregulate cholesterol efflux and dampen inflammatory responses.

### 2.1.3. LXR and coregulators

Nearly 300 nuclear coregulators modulate receptor output by linking ligand-bound LXRs to chromatin-remodeling enzymes (Dasgupta et al., 2014; McKenna et al., 1999).

Ligand structure dictates LBD conformation and, hence, selective recruitment of coactivators versus corepressors (Albers et al., 2006; Belorusova et al., 2019; Berrodin et al., 2010), producing ligand-specific "transcriptional fingerprints" that also depend on cell-type coregulator abundance. For example, TRAP80 is required for SREBF1 induction but dispensable for ABCA1-driven efflux (Kim et al., 2015), illustrating functional "splitting" of the LXR transcriptome (lipogenesis vs. efflux).

Mapping coregulator landscapes across tissues and disease states is therefore essential to design ligands that favor protective programs (anti-inflammatory, cholesterol efflux, autophagy) while avoiding lipogenesis.

### 2.1.4. Transcription selectivity among LXR subtypes

Although LXRα and LXRβ share ~77% identity across DNA- and ligand-binding domains, their distributions differ: LXRα is enriched in liver, intestine, adipose tissue, and macrophages; LXRβ is widely expressed across tissues (Repa et al., 2000; Willy et al., 1995; Song et al., 2022a). Both can activate efflux and lipogenic programs, yet non-redundant roles are clear. In liver, LXRα is the principal driver of SREBP1c-mediated lipogenesis, whereas LXRβ preferentially supports atheroprotective efflux with less lipogenic liability (Bradley et al., 2007; Zhang et al., 2012b). In macrophages engineered to express both isoforms equally, cistromes are partly shared but transcriptomes remain partially distinct, supporting subtype-biased wiring (Ramon-Vazquez et al., 2019). Basal properties also diverge: LXRα shows stronger agonist-driven transactivation, while LXRβ exerts greater basal repression (Bischoff et al., 2010). These nuances underpin the rationale for LXRβ-selective ligands to harness efflux/anti-inflammatory benefits while avoiding hepatic steatosis (Kick et al., 2015; Kick et al., 2016; Schulman, 2017).

Taken together, the interplay of isoform expression, ligand selectivity, and coregulator context establishes a multi-dimensional framework for LXR signaling specificity. This framework underpins ongoing efforts to design subtype- and pathway-selective modulators with therapeutic utility across cardiovascular, metabolic, and neurodegenerative diseases.

## 2.2. LXRs endogenous and synthetic ligands

### 2.2.1. Endogenous ligands

LXRs were identified as receptors for oxysterols (OS). Side-chain OS 22(R)-hydroxycholesterol (22(R)-HC), 24(S)-HC, 25-HC, 27-HC, 24 (S),25-EC are well-validated endogenous agonists that induce both efflux and lipogenic genes (Fig. 3A) (Janowski et al., 1999; Janowski et al., 1996). Importantly, "oxysterol" is not synonymous with "LXR ligand": many OS modulate other nuclear receptors (estrogen receptor α, glucocorticoid receptor, retinoid-related orphan receptor α/γ) or act as enzyme substrates/inhibitors, while major autoxidation products of cholesterol, (7α-HC, 7β-HC, 7-ketocholesterol, 5,6β-epoxycholesterol (5, 6β-EC), Fig. 4A), of 25-HC (Fig. 4B), of 27-HC (Fig. 4C), and autoxidation and hydrolytic products of 24(S),25-EC (Fig. 4D) do not activate LXRs (Janowski et al., 1999; Guillemot-Legris et al., 2016; Guillemot-Legris and Muccioli, 2021; Lehmann et al., 1997; Poirot and Silvente-Poirot, 2013; Schroepfer, 2000).

Conjugated species broaden the endogenous repertoire. 25HC-3S (larsucosterol) (Fig. 3B) inhibits DNMTs and is under clinical evaluation for Non-Alcoholic Steatohepatitis (NASH) and alcoholic hepatitis (Liu et al., 2018; Wang et al., 2020b; Wang et al., 2021). Dendrogenin A (DDA, Fig. 3D), formed from 5,6α-epoxycholestanol (5,6α-EC, Fig. 3C) and histamine, is an LXRβ-biased agonist that promotes redifferentiation, autophagic cell death, and immunogenic vesicle secretion (de Medina et al., 2009; Record et al., 2022; Segala et al., 2017). Among cholesterol precursors, desmosterol (Fig. 3C) behaves as a selective modulator activating efflux in macrophages without lipogenesis in hepatocytes (Muse et al., 2018). The ability of post-lanosterol cholesterol biosynthesis intermediates to modulate LXRs was shown to depend strictly on the presence of a Δ24 double bond (Yang et al., 2006). Taurine (Fig. 3C) has also been reported as an LXRα ligand promoting efflux with minimal lipogenesis (Hoang et al., 2012) and is implicated in healthy aging (McGaunn and Baur, 2023; Singh et al., 2023).

### 2.2.2. LXRs agonists

Synthetic agonists (TO901317, GW3965; Fig. 5A) validate concept by promoting cholesterol efflux, suppressing inflammation, and reversing atherosclerosis in preclinical models (Bradley et al., 2007; Calkin and Tontonoz, 2010). Their limitation is hepatic SREBP1c activation leading to hypertriglyceridemia and steatosis (Repa et al., 2000; Schultz et al., 2000). Because hepatic lipogenesis is largely LXRα-driven and efflux is effectively supported by LXRβ, medicinal chemistry has focused on LXRβ-selective agonists (e.g., LXR-623, XL-041, VTP-38543; ≤10-fold selectivity) (Fig. 5B) that induce RCT genes with reduced lipogenic signals (Quinet et al., 2009), though clinical results remain mixed (see 2.2.8). Structural studies show agonist binding repositions helix 12 and stabilizes coactivator interfaces via isoform-specific His-Trp contacts (El-Gendy et al., 2018; Williams et al., 2003). These insights underpin medicinal chemistry efforts to generate isoform-selective with reduced lipogenic liabilities.

### 2.2.3. LXRs antagonists

Antagonists (e.g., GSK2033, TFCA; Fig. 5C) block coactivator recruitment and blunt agonist-induced transcription (Sim et al., 2015; Zuercher et al., 2010). Given potential risks (e.g., inhibiting peripheral RCT), systemic antagonism has limited appeal, but liver-selective activity (e.g., TFCA) can reduce hepatic lipid accumulation without systemic toxicity (Sim et al., 2015; Sim et al., 2014). GSK2033 reduces ABCA1 in THP-1 cells and lipogenesis in HepG2 cells in vitro (Zuercher et al., 2010), though its broader in vivo pharmacology is context-dependent.

### 2.2.4. LXRs inverse agonists

Inverse agonists (SR9238, SR9243, TLC-2716; Fig. 5D) actively repress basal LXR activity by stabilizing corepressor complexes, silencing lipogenic transcription, and improving steatosis in preclinical
<figure><img src="image_7.png" /><figcaption>**Fig. 3.** Endogenous LXRs ligands including A) agonists: 22(R)-HC: 22(R)-hydroxycholesterol (CID: 167685); 24(S), 25-EC: 24(S),25-epoxycholesterol (CID: 3247059); 24(S)-HC: 24(S)-hydroxycholesterol (CID: 121948); 25-HC: 25-hydroxycholesterol (CID: 65094); 27-HC: 27-hydroxycholesterol (CID: 123976). B) antagonist: 25-HC-3S: 5-Cholesten-3beta-25-diol-3-sulfate (CID: 11583880). C) modulators (SLiMs): 5,6α-EC: 5α,6α-epoxycholestan-3β-ol (CID: 227037); desmosterol: cholest-5,24-dien-3β-ol (CID: 439577); taurine: 2-aminoethanesulfonic acid (CID: 1123) and D) biaised agonist: dendrogenine A: 5α-hydroxy-6β-(2-(1H-imidazol-4-yl)ethylamino)cholestan-3β-ol (CID: 9806490).</figcaption></figure>

<figure><img src="image_8.png" /><figcaption>**Fig. 4.** Oxysterols that are not ligands of LXR including A) B-ring autoxidation products: 7α-HC: 7alpha-hydroxycholesterol (CID: 107722); 7β-hydroxycholesterol (CID: 473141); 7-KC: 7-ketocholesterol (CID: 91474); 5,6β-EC: 5β,6β-epoxycholestan-3β-ol (CID: 440665). B) 25-HC derivatives: 7α,25-diHC: 7α,25-dihydroxycholesterol (CID: 11954197); 7β,25-diHC: 7β,25-dihydroxycholesterol (CID: 473142). C) 27-HC derivatives: 7α,27-diHC: 7α,27-dihydroxycholesterol (CID: 440985); 7β,27-diHC: 7β,27-dihydroxycholesterol (CID: 52931518); 7-K, 27-HC: 7-Keto-27-hydroxycholesterol (CID: 75964209) and D) metabolites of 24(S),25-epoxycholesterol: 24(S),25-diHC: 24(S),25-dihydroxycholesterol (CID: 69331086); 24(R),25-diHC: 24(R),25-dihydroxycholesterol (CID: 10645726); 7α-ol,24(S),25-EC: 7α-hydroxy, 24(S),25-epoxycholesterol (CID: 10549853); 7β-ol,24(S),25-EC: 7β-hydroxy, 24(S),25-epoxycholesterol; 7 K,24(S),25-EC: 7-Keto, 24(S),25-epoxycholesterol.</figcaption></figure>

models (Flaveny et al., 2015; Griffett et al., 2013). Modeling suggests disruption of His435-Trp457 (LXRβ) destabilizes helix 12, enlarging the hydrophobic groove and favoring NCoR1 recruitment (Chen et al., 2020; Elgendy et al., 2022).

### 2.2.5. LXRs biased agonists

Biased agonists engage non-canonical programs. DDA (Fig. 3D) suppresses ABCA1 yet activates lysosome-autophagy and vesicle-secretion pathways via LXRβ, promoting cancer cell redifferentiation and immunogenic small extracellular vesicles (Bauriaud-Mallet et al., 2019; de Medina et al., 2023b; Record et al., 2022; Segala et al., 2017). This shows how structural bias can reveal new therapeutic functions that are different from traditional LXR-dependent transcriptional programs.

### 2.2.6. Transrepressing selective LXR ligands

LXRs can also repress inflammation through a mechanism known as trans-repression (Fessler, 2018; Ghisletti et al., 2007). These insights have motivated the development of transrepression-selective LXR ligands (e.g., GSK9772 and compound 171 (Fig. 5E)) which show anti-inflammatory effects without inducing triglyceride synthesis (Aoyama et al., 2012; Chao et al., 2008; Nomura et al., 2015).

### 2.2.7. Selective LXR modulators (SLiMs)

Analogous to Selective Estrogen Receptor Modulators (SERMs), SLiMs are ligand chemotypes that bias LXR outputs by stabilizing distinct LBD conformations. Sterol-based SLiMs (e.g., desmosterol, 5,6α-EC, Fig. 3C, and DMCHA, MePipHCA, Fig. 5F) preferentially activate efflux in macrophages while sparing hepatocyte lipogenesis (Berrodin et al., 2010; Muse et al., 2018). Non-sterol SLiMs include ouabagenin,
<figure><img src="image_9.png" /><figcaption>**Fig. 5.** Chemical structures of A) synthetic LXRs agonists: TO901317: N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-N-(2,2,2-trifluoroethyl)benzenesulfonamide (CID: 447912) and GW3965: 2-[3-[2-chloro-3-(trifluoromethyl)phenyl]methyl-[2,2-diphenylethyl]amino]propoxy]phenyl]acetic acid (CID: 447905). B) synthetic LXRβ selective agonists: LXR-623: 2-[2-chloro-4-fluorophenyl)methyl]-3-(4-fluorophenyl)-7-(trifluoromethyl)indazole (CID: 16734800); XL-041 (BMS-852927): 2-[2-[2-(2,6-dichlorophenyl)propan-2-yl]-1-[2-fluoro-4-[3-fluoro-4-(hydroxymethyl)-5-methylsulfonylphenyl]phenyl]imidazol-4-yl]propan-2-ol (CID: 49787490) and VTP-38543 (undisclosed CID). C) synthetic LXRs antagonists: GSK2033: 2,4,6-trimethyl-N-[4-(3-methylsulfonylphenyl)phenyl]methyl]-N-[5-(trifluoromethyl)furan-2-yl]methyl)benzenesulfonamide (CID: 46203250) and TFCA: (E)-3-(3,4-dimethoxyphenyl)-N-(4-(trifluoromethyl)phenyl)acrylamide (CID: 329825510). D) synthetic LXRs inverse agonists: SR9238: ethyl 5-[4-(3-methylsulfonylphenyl)phenyl]methyl-(2,4,6-trimethylphenyl)sulfonylamino)methyl]furan-2-carboxylate (CID: 71478195) and SR9243: N-[2-(3-bromophenyl)ethyl]-2,4,6-trimethyl-N-[4-(3-methylsulfonylphenyl)phenyl]methyl)benzenesulfonamide (CID: 76073169). E) Transrepression-Selective LXR ligands (transrepressors): GSK9772: 4-[N-butyl-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)anilino]methyl]-2,6-dichlorophenol (16049480) and 17 L: 2-[2-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]phenyl]isoindole-1,3-dione (CID: 122192273). F) Selective LXR modulators: DMCHA: 3β-Hydroxy-N,N-dimethyl-chol-5-en-24-amide (CID: 24768125); MePipHCA: methylpiperidinyl-3β-hydroxycholenamide (CID undisclosed) and phytochemical LXRs modulator ouabagenin: 3-(1 R,3S,5S,8 R,9S,10 R,11 R,13 R,14S,17 R)-1,3,5,11,14-pentahydroxy-10-(hydroxymethyl)-13-methyl-2,3,4,6,7,8,9,11,12,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2H-furan-5-one (CID: 12313812).</figcaption></figure>

which reduces renal ENaC via LXRβ without hepatic steatosis (Tamura et al., 2018), and taurine (Fig. 3C) (Hoang et al., 2012). Transcriptomics indicates many “agonists” behave as SLiMs, eliciting promoter- and

cell-type-specific responses shaped by coregulator availability (Kim et al., 2015; Ma et al., 2022). Thus, ligand structure and coregulator context ultimately determine whether efflux, anti-inflammatory, or

<table><caption>**Table 1**
LXR ligands tested in clinical trials.</caption><thead><tr><th>Compound</th><th>Ligand</th><th>Clinical phase</th><th>Indication</th><th>Outcomes</th><th>References</th></tr></thead><tbody><tr><td>LXR-623 (WAY-252623)</td><td>LXRβ-selective agonist</td><td>Phase I<br>NCT00379860</td><td>Atherosclerosis</td><td>↑RCT genes in immune cells adverse effects: CNS side effects<br>discontinued</td><td>Katz et al., (2009)</td></tr><tr><td>BMS-779788</td><td>LXRβ-selective agonist</td><td>Phase I<br>NCT00836602</td><td>Atherosclerosis</td><td>Discontinued<br>(undisclosed reason)</td><td>Unpublished</td></tr><tr><td>BMS-852927 (XL041)</td><td>LXRβ-selective agonist</td><td>Phase I<br>NCT01651273</td><td>Atherosclerosis</td><td>↑ RCT genes; adverse effects: ↑TG, ↑LDL, ↓neutrophils; discontinued</td><td>Kirchgessner et al., (2016)</td></tr><tr><td>CS-8080</td><td>LXRβ-selective agonist</td><td>Phase I<br>NCT00796575</td><td>Atherosclerosis</td><td>Discontinued<br>(undisclosed reason)</td><td>Unpublished</td></tr><tr><td>VTP-38543</td><td>LXRβ-selective agonist</td><td>Phase IIa<br>NCT02655679</td><td>Atopic dermatitis</td><td>Improved skin barrier function; trial completed</td><td>Czarnowicki et al., (2018)</td></tr><tr><td>Rovazolac (ALX-101)</td><td>LXRβ-selective agonist</td><td>Phase IIb<br>NCT03175354</td><td>Atopic dermatitis</td><td>Not described</td><td>Unpublished</td></tr><tr><td>RGX-104</td><td>LXR agonist</td><td>Phase I<br>NCT02922764</td><td>Cancer</td><td>↓MDSC<br>DC stimulation<br>CTL activation</td><td>Mita et al. (2018)</td></tr><tr><td>TLC-2716</td><td>LXR inverse agonist</td><td>Phase IIa<br>NCT06564584</td><td>Hypertriglyceridemia,<br>NAFLD</td><td>↓ TG and LDL<br>No effect on RCT<br>Phase IIa trial ongoing</td><td>Unpublished</td></tr><tr><td>Larsu costerol (DUR-928; 25HC-3S)</td><td>LXR antagonist</td><td>Phase IIb<br>NCT04563026</td><td>Alcoholic hepatitis</td><td>↓ bilirubin<br>MELD score improvement</td><td>Hassanein et al., (2024)</td></tr></tbody></table>

CNS: central nervous system; CTL: cytotoxic T cells; DC: dendritic cells; LDL: low density lipoprotein; LXR: Liver X Receptor; MDSC: myeloid derived suppressing cells; MELD: model for end-stage liver disease; NAFLD: non-alcoholic fatty liver disease; RCT: reverse cholesterol transport; TG: triglycerides.
lipogenic modules dominate.

### 2.2.8. LXRs and clinical trials

Preclinical validation has not yet translated seamlessly to the clinic (Table 1). Four partially LXRβ-selective agonists LXR-623 (WAY-252623), BMS-779788, BMS-852927 (XL041), and CS-8080 entered Phase I primarily for atherosclerosis, aiming to leverage LXRβ-mediated RCT while avoiding LXRα-driven lipogenesis (Kick et al., 2015; Kick et al., 2016; Kirchgessner et al., 2015). LXR-623 increased ABCA1/ABCG1 in circulating immune cells but was discontinued due to unexpected CNS adverse effects (Katz et al., 2009). BMS-852927 drove RCT-associated genes in preclinical species yet, in humans, increased plasma triglycerides and LDL-C and caused neutropenia (Kirchgessner et al., 2016). Programs for BMS-779788 and CS-8080 were halted without detailed disclosure (Fessler, 2018).

To preserve vascular and anti-inflammatory benefits while minimizing metabolic liabilities, next-generation strategies include: SLiMs that bias toward macrophage efflux/anti-inflammatory programs while sparing hepatic lipogenesis (Muse et al., 2018); and trans-repression-selective ligands that suppress inflammatory cascades without robustly activating lipogenesis (Aoyama et al., 2012; Chao et al., 2008; Nomura et al., 2015). Beyond cardiovascular disease, VTP-38543 showed efficacy in Phase II for atopic dermatitis (Czarnowicki et al., 2018); the LXRβ agonist RGX-104 is in oncology trials as an immunomodulatory agent that depletes myeloid-derived suppressor cells (Tavazoie et al., 2018). In metabolic disease, the inverse agonist TLC-2716 and the antagonist larsucosterol (25-HC-3S, DUR-928) are currently in Phase II testing for non-alcoholic fatty liver disease (NAFLD) and alcoholic hepatitis respectively (Table 1). Preliminary clinical data indicate that larsucosterol may contribute to improvement of hepatic function in patients with alcoholic hepatitis (Hassanein et al., 2024). Together, these experiences underscore the double-edged nature of LXR pharmacology: systemic pan-agonism is untenable, but subtype-selective, biased, trans-repression-favoring, or tissue-targeted approaches remain compelling.

Accordingly, translational endpoints and pharmacology should look beyond RCT, lipids, and inflammation resolution, to encompass autophagy-lysosome competence, mitochondrial resilience, endocrine/neuronal signaling, and vesicle-mediated intercellular communication domains where LXR ligands can deliver disease-relevant benefit.

## 3. LXR and aging

### 3.1. LXRs, genes polymorphisms and aging

LXRα polymorphisms have been identified, and one haplotype has been associated with increased human lifespan, mainly due to decreased mortality from infectious diseases (Mooijaart et al., 2007). Interestingly, LXRs are close mammalian homologs of the Caenorhabditis elegans nuclear receptor dauer formation 12 (DAF-12) and nuclear hormone receptor 8 (NHR-8) (Antebi, 2015). These receptors bind 3-keto bile acid-like steroids, known as dafachronic acids, to regulate the developmental decision between reproductive growth and lifespan extension (Gerisch et al., 2007; Thondamal et al., 2014).

These observations suggest that the pathways involving dafachronic acids/DAF-12 in nematodes and oxysterols/LXRs in mammals are evolutionarily conserved mechanisms that regulate reproduction and aging.

In addition, polymorphisms in LXR-responsive genes encoding cholesterol ester transfer protein (CETP) and apolipoprotein E (APOE) have been associated with longevity. CETP influences lipoprotein composition, size, and number by mediating the bidirectional exchange of cholesteryl esters and triglycerides between lipoproteins (Zhang et al., 2012a). Notably, CETP inhibitors are being explored as potential therapeutic agents for cardiovascular disease (Schmidt et al., 2021). The frequency of the CETP I405V polymorphism is increased among

individuals with exceptional longevity. This variant is associated with reduced CETP activity and a healthy aging phenotype characterized by lower prevalence of hypertension, cardiovascular disease, and metabolic syndrome (Barzilai, 2003).

ApoE, another LXR-responsive gene, exists as three major haplotypes ε2, ε3, and ε4 that influence human longevity. Beyond its critical role in lipoprotein metabolism and clearance from plasma, ApoE participates in neuronal plasticity, triglyceride storage, inflammation, and hormone production (Martinez-Martinez et al., 2020). In humans, ApoE3, encoded by the ε3 allele, is the most common isoform. By contrast, the ApoE4 isoform decreases the likelihood of achieving extreme longevity and is a major genetic risk factor for age-related diseases, particularly Alzheimer's disease (Garatachea et al., 2014; Yamazaki et al., 2019). However, ApoE4 has been associated with higher fertility in women, indicating a possible reproductive advantage (Trumble et al., 2023; van Exel et al., 2017). These findings may explain the evolutionary persistence of the ancestral ε4 allele and align with the antagonistic pleiotropy theory of aging, which posits that genes conferring early-life benefits can have detrimental effects later in life (Bapteste et al., 2023; Williams, 2001). Conversely, the ApoE2 isoform occurs more frequently in cen-tenarians (Shinohara et al., 2020) but has been associated with reduced fertility.

Taken together, these findings suggest that LXRs and their target genes CETP and ApoE are key determinants of human longevity and exemplify the evolutionary trade-offs between metabolic fitness, reproduction, and aging.

### 3.2. LXRs and aging hallmarks regulation are interconnected

The hallmarks of aging provide a unifying framework to understand the biological processes that drive organismal decline (Biga et al., 2025; Lopez-Otin et al., 2023a; López-Otin et al., 2013; Lopez-Otin et al., 2023b). LXRs intersect with multiple hallmarks, suggesting they may represent actionable targets for delaying age-associated dysfunction (Table 2 and Fig. 6).

#### 3.2.1. Hallmark 1: genomic instability

##### 3.2.1.1. Genomic instability and aging.
Accumulation of DNA damage and defects in nuclear architecture are central drivers of aging. Mutations in genome maintenance pathways cause progeroid syndromes such as Werner syndrome, Hutchinson-Gilford progeria, and Cockayne syndrome (Milosic et al., 2023; Navarro et al., 2006). Mitochondrial DNA instability similarly accelerates degenerative phenotypes.

##### 3.2.1.2. LXRs and genome maintenance.
Evidence linking LXRs to genome stability is emerging. In pancreatic cancer cells, the LXRα-SREBF1 axis regulates the DNA repair enzyme polynucleotide kinase/phosphatase (PNKP); genetic or pharmacological LXR inhibition reduces PNKP expression, increases DNA double-strand breaks, and induces apoptosis (Yang et al., 2020). Notably, loss of PNKP in mice causes a premature aging-like phenotype (Shin et al., 2021). In the liver, nuclear lamina defects associated with aging or laminopathies derepress LXR-dependent genes via increased Foxa2 occupancy, leading to steatosis (Whitton et al., 2018). Moreover, ApoE has been shown to promote lamin degradation through autophagy-lysosome pathways, destabilizing heterochromatin and driving senescence in mesenchymal stem cells (Zhao et al., 2022). Collectively, these findings suggest LXRs influence genomic stability through DNA repair regulation and nuclear architecture maintenance.

#### 3.2.2. Hallmark 2: epigenetic alterations

##### 3.2.2.1. Epigenetics and aging.
Epigenetic modifications (e.g., DNA methylation, histone post-translational modifications, and chromatin
<table><caption>**Table 2**
Impact of LXRs modulation in the hallmarks of ageing.</caption><thead><tr><th>Hallmarks of ageing</th><th>Pharmacological/genetic interventions</th><th>Effects</th><th>Models</th><th>References</th></tr></thead><tbody><tr><td>Genomic instability</td><td>GW3965 (10 µM)<br>LXRα overexpression<br>Triptonide (8 nM)<br>LXRα silencing<br>Nuclear lamina abnormalities</td><td>↑ PNPK,<br>↑ DNA repair<br>↓ PNPK,<br>↓ DNA repair<br>De-repression of LXR-dependent genes expression, fatty liver</td><td>Human pancreatic cancer cells</td><td>(Yang et al., 2020)</td></tr><tr><td>Epigenetic alterations</td><td>Maternal protein restriction<br>TO901317 (10 µM)<br>LXRα/β silencing</td><td>LXRα promoter hypermethylation, ↓ LXRα mRNA<br>↑ JMJD2B expression<br>↑ JMJD2B-dependent lipogenic genes expression<br>↑ EZH2 expression<br>↑ methylation of H3K27 of the promoters of Msmb and Nkx3.1<br>↓ expression of Msmb and Nkx3.1 prostatic intra-epithelial neoplasia</td><td>Liver (aged mice; Zmpste24 KO mice)<br>Fetal mice liver</td><td>(Whitton et al., 2018)<br>(van Straten et al., 2010)</td></tr><tr><td></td><td>GW3965 (50 mg/Kg/day)<br>TO901317, GW3965 (1 µM)<br>DDA (1–5 µM)</td><td>Change in DNA methylation and increased expression of synapse related genes<br>↓ visfatin expression<br>↓ NAD+ level<br>↑ LC3A/B, TFEB<br>↓ P70S6K<br>Lethal autophagy</td><td>HepG2 cells<br>C57BL/6 J mice liver<br>WT and LXRα/LXRβ DKO mice</td><td>(Kim et al., 2020)<br>(Pommier et al., 2013)</td></tr><tr><td>Disabled macroautophagy & deregulated nutrient sensing</td><td>TO901317, GW3965, XL-041<br>27-HC (2.5 µM), GW3965 (10 µM)<br>CYP27A1 silencing</td><td>↑ mTor,<br>↓ AMPK/sirtuin<br>Autophagy suppression<br>↑ autophagic flux<br>↓ autophagic flux</td><td>Human acute myeloid leukemia<br>Melanoma, breast cancer</td><td>(Segala et al., 2017); (Mouchel et al., 2020)</td></tr><tr><td>Cellular senescence</td><td>TO901317<br>GW3965<br>GW3965<br>LXRα silencing</td><td>↓ senescence induced by high glucose<br>↑ CD38, P16, P21 expression<br>↓ Chol and IR induced CD38 expression</td><td>Mouse podocytes<br>Diabetic mice</td><td>(Zhang et al., 2020)</td></tr><tr><td>Mitochondrial dysfunction</td><td>GW3965<br>TO901317<br>LXR623<br>GW3965<br>SR9243<br>LXRα silencing</td><td>↓ HG induced mitochondrial fission, reduction of ETC complexes expression and apoptosis.<br>↓ β-amyloid induced reduction of mitochondrial biogenesis and ATP production.<br>↓ ATP level, respiratory complexes expression and mitochondrial respiration<br>↓ mitochondrial respiration<br>↑ mitochondrial respiration and basal glycolytic rate</td><td>Human primary macrophages<br>Human umbilical vein endothelial cells; diabetic rats<br>BMDM</td><td>(Saliba-Gustafsson et al., 2019)<br>(Hayashi et al., 2014)<br>(Terao et al., 2024)</td></tr><tr><td>Chronic inflammation</td><td>GW3965<br>TO901317<br>LXRα/β silencing<br>22(R)-HC (2 µM; 5 µM)<br>24(S)-HC (5 µM)<br>24(S),25-EC (5 µM)<br>27-HC (5.6 µM)<br>TO901317 (1 µM), GW3965 (1 µM)+LG268 (50 nM)<br>GW3965 (1 µM)</td><td>↓ LPS-induced iNOS, IL6, IL1β, COX2 expression and NF-κB promoter activity<br>↓ TNFα or IL1β-induced iNOS and IL6, expression<br>↑ LPS induced iNOS, TNFα, IL6<br>↓ LPS-induced iNOS<br>↑ IL10 release<br>↑ ArgII expression<br>↑ apoptotic cells engulfment and Mer expression</td><td>Rat cardiomyocytes<br>Human neural stem cells<br>Human glioblastoma and colon cancer cells<br>CD8 + T cells<br>Murine peritoneal macrophages<br>mixed background mice (C57BL/6 and 129 Sv)<br>LXRα/LXRβ DKO mice<br>Murine peritoneal macrophages</td><td>(Lin et al., 2022)<br>(Chiang et al., 2022)<br>(Nguyen et al., 2019)<br>(Carpenter et al., 2019)<br>(Joseph et al., 2003)<br>(Ghisletti et al., 2007; Joseph et al., 2003)</td></tr><tr><td>Stem cells exhaustion</td><td>22(R)-HC (0.1–1 µM)<br>LXRα and LXRβ silencing<br>22(R)-HC (0.5–3 µM)</td><td>↓ apoptotic cells engulfment and ↓ efferocytosis induced Mer, IL-10 and TGFβ1<br>Development of age-dependent autoimmune diseases (↑ autoantibodies from 40 weeks old mice)<br>↑ SPMDLA3 expression and cGAMP degradation; ↓ cGAMP induced STING signaling and INFβ, CXCL10 and CCL5 expression.<br>↑ Tuj1 and TH positive cells (neurogenesis)<br>↑ neurites and axon length (Neurons like morphology), MAP2, TH, nestin, tuj1, synaptophysin, DAT</td><td>Human macrophage (M0)<br>RAW264.7 stably transfected with LXRα; murine peritoneal macrophages<br>RAW cells; Murine peritoneal macrophages; WT and LXRα/LXRβ DKO mice (liver and spleen)<br>peritoneal macrophages from WT and LXRα/LXRβ DKO mice<br>Murine primary BMDM; C57BL/6 mice (liver and spleen)<br>Human embryonic stem cells<br>E11.5 WT and LXRα/LXRβ DKO mice (ventral midbrain)<br>hMSC from BM, AD and DP.</td><td>(Marengo et al., 2016)<br>(Marathe et al., 2006)<br>(A-Gonzalez et al., 2009)<br>(Hou et al., 2023)<br>(Sacchetti et al., 2009)<br>(Singh et al., 2021)</td></tr></tbody></table>

(continued on next page)
<table><caption>**Table 2 (continued)**</caption><thead><tr><th>Hallmarks of ageing</th><th>Pharmacological/genetic interventions</th><th>Effects</th><th>Models</th><th>References</th></tr></thead><tbody><tr><td></td><td>Transplantation of hMSC exposed to 22(R)-HC</td><td>Recovery of motor functions</td><td>Wistar rat PD model</td><td></td></tr><tr><td></td><td>LXRβ silencing</td><td>Dentate gyrus hypoplasia, ↓ Sox2, Notch1 and synaptophysin, impaired social interaction.</td><td>LXRβ KO mice</td><td>(Cai et al., 2018)</td></tr><tr><td></td><td>DDA 0.01 µM</td><td>↑ proliferation and neuronal differentiation</td><td>Murine neural stem cells</td><td>(Khalifa et al., 2014)</td></tr><tr><td></td><td>LXRα and LXRβ silencing</td><td>↑ LD accumulation, PPARγ, FAS, ↓ Wnt/β-catenin</td><td>Murine MSC from LXRα/LXRβ DKO mice and WT C57BL/6 mice</td><td>(Matsushita et al., 2016)</td></tr><tr><td></td><td>LXRα overexpression</td><td>↓ LD accumulation, PPARγ, FAS</td><td>Murine MSC</td><td>(Kim et al., 2010)</td></tr><tr><td></td><td>20(S)-HC (5 µM)</td><td>↑ osteogenic genes (Notch, HES-1, HEY-1)</td><td>Chronic cerebral hypoperfusion mice model</td><td>(Sun et al., 2018)</td></tr><tr><td></td><td>GW3965 (10 mg/Kg)</td><td>↑ neuronal survival in the hippocampus and prefrontal cortex recovery of adult neurogenesis.</td><td>C57BL/6 J mice (colonic tissue and SI crypts)</td><td>(Das et al., 2025)</td></tr><tr><td></td><td>TBI (10 Gy) or DSS induced colitis</td><td>↑ LXR target genes expression (Abca1, Apoc3, Apoa1 and Apoa4, Sult2B1)</td><td></td><td></td></tr><tr><td></td><td>GW3965 (50 mg per Kg)+ TBI (10 Gy) or DSS</td><td>↑ olfm4 (ISC marker) and AREG expression, ↑ intestinal crypt cell proliferation, colon length and organoids budding. Inhibition of GW395 pro-regenerative activity by LXR, CYP27A1 and AREG deletion.</td><td></td><td></td></tr><tr><td>Cell-cell communication</td><td>TO901317 (5 mg/ml; oral gavage)</td><td>↑ plasma corticosterone, ↑ adrenal steroidogenesis genes (StAR, CYP11A1, HSD3B1, ACTH receptor)</td><td>WT and LXRα/LXRβ DKO mice (plasma and adrenals)</td><td>(Steffensen et al., 2004)</td></tr><tr><td></td><td>LXRα and LXRβ silencing</td><td>↑ HSD11B1 expression</td><td>WT and LXRα/LXRβ DKO mice (pituitary)</td><td>(Nilsson et al., 2007)</td></tr><tr><td></td><td>GW3965 (0.025 % wt/wt)</td><td>↑ Serum ACTH</td><td>MIN6 cells, HIT-T15 cells and isolated mouse pancreatic islets</td><td>(Meng et al., 2012)</td></tr><tr><td></td><td>LXRα and LXRβ silencing</td><td>↓ GSIS</td><td>C57BL/6 J mice</td><td></td></tr><tr><td></td><td>TO901317 (0.1–10 µM for 2 days)+high glucose</td><td>↓ GSIS, ↑ plasma glucose</td><td>MIN6 cells and isolated rat islets; INS-1 cells</td><td>(Zitzer et al., 2006)<sup>a</sup> (Efanov et al., 2004)<sup>a</sup></td></tr><tr><td></td><td>TO901317 (50 mg/day; 7 days)+glucose injection</td><td></td><td></td><td>(Green et al., 2009)<sup>b</sup></td></tr><tr><td></td><td>TO901317 (1 µM for 3 days<sup>a</sup> or 10 µM for 2 days<sup>b</sup>)+high glucose</td><td>↑ GSIS, ↑ PDX1 and ins2 expression.</td><td>Mouse primary hepatocyte HEPG2</td><td>(Uebanso et al., 2012)</td></tr><tr><td></td><td>TO901317 (0.1–1 µM)</td><td>↓ FGF21</td><td>Human and murine melanoma cell lines (SKMEL28 and B16F10)</td><td>(Record et al., 2022; de Medina et al., 2023a; de Medina et al., 2023b)</td></tr><tr><td></td><td>DDA (0.01–2 µM)</td><td>↑ sEV production<br>Change in sEV composition: ↑ BMP, Tyrosinase, TRP2, Melan A, Rab27a and b, calreticulin.<br>DDA sEV: ↑ DC maturation and antitumoral.</td><td></td><td></td></tr></tbody></table>

ACTH: adrenocorticotropic hormone; AD: adipose tissue; ArgII: arginaseII; AREG: amphiregulin; BM: bone marrow; BMDM: bone marrow derived macrophage; BMP: bis(monoacylglycerol)phosphate; CCL5: chemokine (C-C motif) ligand 5; CXCL10: chemokine (C-X-C motif) ligand 10; cGAMP: cyclic GMP-AMP; COX2: cyclooxygenase-2; DAT: Dopamine Transporter; DC: dendritic cells; DP: dental pulp; DSS: dextran sodium sulfate; ETC: electron transport chain; EZH2: Enhancer of Zeste Homolog 2; FAS: fatty acid synthase; FGF: Fibroblast Growth Factor; GFAP: Glial Fibrillary Acidic Protein; GSIS: glucose-stimulated insulin secretion; HG: high glucose; iNOS: inducible nitric oxide synthase; IR: irradiation; ISC: intestinal stem cells; JMJD2B: Jumonji Domain-Containing Protein 2B; LD: lipid droplet; LXRα/LXRβ DKO mice: Nr1h3-/-Nr1h2-/- mixed background mice (C57BL/6 and 129 Sv); Msmb: Microseminoprotein Beta; NAD: Nicotinamide Adenine Dinucleotide; Nkx3.1: NK3 Homeobox 1; MAP2: Microtubule-Associated Protein 2; Mer: MER Tyrosine Kinase; MSC: mesenchymal stem cells; olmf4: Olfactomedin 4; PD: Parkinson disease; PDX1: Pancreatic and Duodenal Homeobox 1; PNPK: Polynucleotide Kinase 3'-Phosphatase; PPAR: Peroxisome Proliferator-Activated Receptor; Rab27: Ras-related protein Rab-27; sEV: small extracellular vesicles; SHH: Sonic Hedgehog; SI: small intestine; Sox2: SRY (Sex-determining Region Y)-box 2; SPMDLA3: sphingomyelin phosphodiesterase acid-like 3 A; StAR: Steroidogenic Acute Regulatory Protein; STING: Stimulator of Interferon Genes; TBI: total body irradiation; TFEB: Transcription Factor EB; TH: Tyrosine Hydroxylase; TRP2: Tyrosinase-Related Protein 1; Tuj1: Tubulin, beta class I; WT: wild type.

remodeling) govern transcriptional programs without altering the genetic code. With age, characteristic changes occur, including global DNA hypomethylation, focal hypermethylation, and altered histone marks, all of which are linked to functional decline and disease (Bannister and Kouzarides, 2011; Goldberg et al., 2007). Epigenetic clocks based on DNA methylation can predict biological age, while interventions such as dietary restriction, rapamycin, and heterochronic parabiosis mitigate age-associated epigenetic drift (Bell et al., 2019; Cole et al., 2017).

### 3.2.2.2. LXRs and epigenetic regulation.
LXRs shape chromatin architecture through coactivator/corepressor recruitment. Prenatal stress induces hypermethylation of the LXRα promoter in offspring, predisposing them to metabolic disease (Martinez et al., 2014; Rodrigo et al., 2018; van Straten et al., 2010). Pharmacological activation by TO901317 upregulates the histone demethylase JMJD2B, which partners with LXRα to demethylate H3K9me2/3 at LXREs, driving lipogenic transcription (Kim et al., 2020). Conversely, Lxrα/β double knockout increases EZH2 activity in the prostate, enhancing H3K27me3 at tumor suppressor loci and promoting neoplasia (Pommier et al., 2013). In neurodegenerative models, GW3965 alters methylation at genes linked to synaptogenesis and neurogenesis (Sandoval-Hernandez et al., 2016a;

Sandoval-Hernandez et al., 2016b).

LXRs also influence availability of metabolites that feed into epigenetic enzymes. For example, TO901317 and GW3965 downregulate visfatin and intracellular NAD+, with potential consequences for sirtuin activity (Mayi et al., 2011; Terao et al., 2024). OS derivatives likewise exert opposing epigenetic effects: 25-HC induces DNMT1, whereas its sulfated metabolite 25-HC-3S (larsu costerol) inhibits DNMTs, a property now being tested clinically in NASH and alcoholic hepatitis (Liu et al., 2018; Wang et al., 2020a; Wang et al., 2020b; Wang et al., 2024). Intriguingly, the enzymes that generate these metabolites (CH25H and SULT2B1) are themselves transcriptional targets of LXRs (Jiang et al., 2005; Wang et al., 2021).

Together, these findings reveal a bidirectional relationship: LXRs are both epigenetic regulators and targets of epigenetic modification, positioning them at a critical intersection between metabolism, chromatin state, and aging.

### 3.2.3. Hallmark 3: autophagy and nutrient sensing

#### 3.2.3.1. Autophagy and aging.
Autophagy is a conserved catabolic process that maintains homeostasis by degrading and recycling damaged
LXRs and the hallmarks of aging

<figure><img src="image_10.png" /><figcaption>**Fig. 6.** Relationship between LXRs and the hallmarks of aging.</figcaption></figure>

organelles, misfolded proteins, and other cellular components (Mizushima et al., 2008). With age, autophagic efficiency declines, predisposing tissues to proteotoxicity, metabolic dysfunction, and degeneration. Impaired autophagy is linked to multiple age-related pathologies, whereas interventions such as caloric restriction, rapamycin, spermidine, metformin, and NAD+ supplementation enhance autophagic flux and extend lifespan (Leidal et al., 2018; Ren and Zhang, 2018). Nutrient-sensing pathways tightly regulate autophagy and aging: mTOR activation inhibits autophagy and accelerates aging, whereas AMPK and sirtuins promote autophagy and are associated with anti-aging effects (Ge et al., 2022; López-Otin et al., 2013; Wu et al., 2024).

### 3.2.3.2. LXRs and autophagy regulation.
LXRs intersect with autophagy in a ligand-dependent manner. The endogenous metabolite dendrogenin A (DDA) induces autophagy via LXRβ by upregulating NR4A1, LC3A/B, ATG3, and TFEB (Mouchel et al., 2020; Segala et al., 2017; Serhan et al., 2020). Both NR4A1 and TFEB are considered anti-aging transcription factors: NR4A1 regulates immune tolerance and neuroprotection, while TFEB orchestrates lysosomal biogenesis and autophagy programs (Abokyi et al., 2023; Paillasse and de Medina, 2015). DDA derepresses TFEB by reducing LXRβ occupancy at a TFEB enhancer, whereas oxy sterols such as 22(R)-HC exert opposite effects (Segala et al., 2017).

Conversely, synthetic agonists (TO901317, GW3965), and β-selective (XL041) ligands have been shown to suppress autophagy in podocytes by reducing AMPK and sirtuin activity while activating mTOR (Zhang et al., 2020). Reciprocal crosstalk exists with nutrient sensing pathways that drive autophagy and aging: SIRT1 deacetylates and activates LXR, while AMPK enhances LXRα activity toward efflux genes but inhibits lipogenic transcription (Kemmerer et al., 2016; Li et al., 2007; Yap et al., 2011). Moreover, genetic variants such as a PLIN2 Pro251 allele create feedback loops between LXRs and autophagy by enhancing 27-HC pro- duction, LXR activity, cholesterol efflux and autophagy (Saliba-Gustafsson et al., 2019).

Thus, LXRs function at the interface of autophagy, nutrient sensing, and metabolism, with outcomes dependent on ligand structure and cellular context. Biased agonists like DDA may promote beneficial autophagy programs, whereas pan-agonists can suppress them.

### 3.2.4. Hallmark 4: cellular senescence

#### 3.2.4.1. Aging and senescence.
Senescence is a terminal growth arrest triggered by telomere attrition, DNA damage, oxidative stress, oncogene activation, and mitochondrial dysfunction (Khosla et al., 2020). Senescent cells accumulate with age and secrete pro-inflammatory factors collectively termed the senescence-associated secretory phenotype (SASP), which contributes to inflamming and tissue dysfunction (Franceschi and Campisi, 2014). Senescence is now recognized as both a hallmark and a driver of chronic age-related diseases, including cancer, cardiovascular disease, and neurodegeneration (Coppé et al., 2010; Kirkland and Tchkonia, 2017). Therapeutically, senolytics (e.g., dasatinib + quercetin) and senomorphics (SASP inhibitors) are under active clinical development for age-related disorders (Khosla et al., 2020; Robbins et al., 2021).

#### 3.2.4.2. LXRs and senescence.
LXRs modulate senescence in a cell-type-specific manner. In endothelial cells exposed to high glucose, synthetic agonists (TO901317, GW3965) reduce oxidative stress, telomere shortening, and senescence via LXRβ and SREBF1 (Hayashi et al., 2014). By contrast, in macrophages, LXRα activation induces CD38 expression under metabolic or genotoxic stress, leading to NAD+ depletion and senescence (Terao et al., 2024). Interestingly, the endogenous oxysterol 25-HC has been reported to exert senolytic effects, though the involvement of LXRs remains to be defined (Limbad et al., 2022).

Together, these findings position LXRs as context-dependent regulators of senescence. Depending on isoform expression and ligand engagement, LXRs may either suppress stress-induced senescence (e.g., in endothelium) or promote it (e.g., in metabolically stressed macrophages). This duality underscores the importance of isoform-selective and biased ligands for therapeutic exploitation in age-related pathologies linked to cellular senescence.

### 3.2.5. Hallmark 5: mitochondrial dysfunction

#### 3.2.5.1. Mitochondria and aging.
Mitochondrial decline is a well-established hallmark of aging, contributing to sarcopenia,
cardiovascular dysfunction, neurodegeneration, and metabolic disease (Lopez-Otin et al., 2023a; López-Otin et al., 2013). Aging is associated with reduced mitochondrial mass, altered dynamics, accumulation of mtDNA mutations, and impaired respiratory chain efficiency (DeBalsi et al., 2017; Gonzalez-Freire et al., 2015). Mice harboring defective mtDNA polymerase accumulate mutations, exhibit respiratory insufficiency, and develop premature aging phenotypes including sarcopenia, cardiomyopathy, and reduced lifespan (Trifunovic et al., 2004). Conversely, interventions such as exercise, metformin, and NAD+ precursors promote mitochondrial biogenesis and delay aging (Srivastava, 2016). A measurable decline in resting energy expenditure of ~1–2% per decade in humans highlights the progressive erosion of mitochondrial function with age (Manini, 2010).

### 3.2.5.2. LXRs and mitochondrial function.
LXRs influence mitochondrial biogenesis and metabolism in a context-dependent manner. The agonist GW3965 protects cardiomyoblasts against high-glucose-induced mitochondrial damage (Lin et al., 2022). TO901317 restores mitochondrial mass, ATP production, and expression of biogenesis genes in neural stem cells exposed to amyloid-β (Chiang et al., 2022). In immune and cancer systems, LXRs alter bioenergetics: silencing LXRα or treating with the inverse agonist SR9243 increases CD8+ T-cell mitochondrial metabolism toward enhanced antitumor activity (Carpenter et al., 2019), while the partial agonist LXR-623 reduces oxygen consumption and ATP production in glioblastoma by downregulating respiratory complex proteins (Nguyen et al., 2019).

These findings suggest that LXRs regulate mitochondrial integrity across diverse cell types, often aligning with protective or reparative outcomes. However, effects differ by ligand and tissue context, underscoring the need for biased agonist or SLiMs to harness mitochondrial benefits without off-target liabilities.

### 3.2.6. Hallmark 6: chronic inflammation

#### 3.2.6.1. Inflammation and aging.
Acute inflammation is an essential host defense mechanism, but its resolution is equally critical. With age, the immune system shifts toward a state of chronic low-grade inflammation ("inflammaging"), characterized by persistent cytokine production, innate immune activation, and impaired resolution (Franceschi et al., 2018b). Inflammaging is both a hallmark and a driver of age-related disease, linked to genomic instability, mitochondrial dysfunction, impaired autophagy, and dysbiosis, which create reinforcing loops of damage (Baechle et al., 2023). Pharmacological suppression of chronic inflammation shows therapeutic promise: etanercept (anti-TNFα) prevents sarcopenia and cognitive decline in aged mice (Sciorati et al., 2020), and the anti-IL-1β antibody canakinumab reduces recurrent cardiovascular events in humans (Ridker et al., 2017).

#### 3.2.6.2. LXRs and inflammation.
LXRs are potent modulators of inflammatory tone. Synthetic (TO901317 and GW3965) and endogenous (22(R)-HC, 24(S),25-EC, 24(S)-HC) LXRs agonists suppress expression of iNOS, COX2, and proinflammatory cytokines in macrophages and in vivo (Ghisletti et al., 2007; Joseph et al., 2003). Mechanisms include SUMOylation-dependent transrepression; cis-repression at inflammatory enhancers; polyunsaturated fatty acids biogenesis and phospholipid remodeling that dampen toll like receptors (TLRs) signaling; and induction of SMPDL3A, which inhibits the cGAS-STING pathway (Castrillo et al., 2003; Ghisletti et al., 2007; Hou et al., 2023; Rong et al., 2013; Thomas et al., 2018). LXRs also promote M2 macrophage polarization and induce MerTK, enhancing efferocytosis and resolution (Marathe et al., 2006; N et al., 2009; Marengo et al., 2016). Notably, reciprocal crosstalk exists: TLR signaling dampens LXR activity (Zelcer and Tontonoz, 2006), potentially explaining reduced efficacy in chronic inflammatory settings. However, some reports also showed that inflammation can be induced by LXRs activation (Asquith et al., 2009; Fontaine et al., 2007; Torocsik et al., 2010; Jang et al., 2016), suggesting that further studies are needed for a better understanding of the relationship between LXRs and inflammation.

Collectively, these findings highlight LXRs as integrators of lipid metabolism and inflammation, capable of restraining inflamming through multiple mechanisms. Strategies that bias toward transrepression and efferocytosis programs, while sparing lipogenic pathways, hold particular promise for treating age-related inflammatory disease.

### 3.2.7. Hallmark 7: stem cell exhaustion

#### 3.2.7.1. Stem cells and aging.
Tissue regeneration depends on the ability of stem cells to self-renew and differentiate, as well as the plasticity of somatic cells to dedifferentiate after injury. With age, these processes decline, leading to impaired repair capacity, tissue dysfunction, and frailty (Behrens et al., 2014; Goodell and Rando, 2015). Stem cell dysfunction reflects the cumulative impact of other hallmarks, including senescence, DNA damage, and epigenetic alterations. Interventions such as partial cellular reprogramming with Yamanaka factors (OCT4, SOX2, KLF4, MYC) restore regenerative potential and extend lifespan in mice. This highlights stem cell exhaustion as both a hallmark and a therapeutic target in aging biology.

#### 3.2.7.2. LXRs and stem cell biology.
LXRs regulate stem and progenitor cell fate. The oxysterol 22(R)-HC promotes dopaminergic neuron differentiation from mesenchymal and embryonic stem cells (Sacchetti et al., 2009; Singh et al., 2021). Deletion of LXRβ impairs hippocampal neurogenesis and progenitor maintenance, whereas dendrogenin A (DDA) stimulates neural stem cell proliferation and differentiation (Cai et al., 2018; Khalifa et al., 2014). LXRα activation inhibits adipogenesis via Wnt/β-catenin signaling while 20(S)-HC promotes osteogenic differentiation through LXRs and hedgehog pathways, suggesting a role in protecting against age-related osteoporosis (Kim et al., 2010; Matsushita et al., 2016).

In regeneration, LXR signaling enhances neurogenesis and recovery after central nervous system injury and promotes intestinal regeneration while preventing tumorigenesis, indicating that LXRs may act as a regeneration-tumorigenesis rheostat, potentially mediated by CYP27A1-derived oxysterols (Cui et al., 2017; Das et al., 2025; Sun et al., 2018; Zhang et al., 2023b).

Overall, LXRs influence stem cell maintenance, lineage fate, and regenerative responses, placing them at a crucial interface between stem cell exhaustion and age-related disease.

### 3.2.8. Hallmark 8: altered intercellular communication

#### 3.2.8.1. Intercellular communication and aging.
Intercellular communication ensures coordination of tissue and systemic homeostasis through juxtacrine (cell junctions, nanotubes), paracrine (soluble factors, synaptic signaling, extracellular vesicles), and endocrine/neuroendocrine pathways. With aging, these systems are altered: secretory SASP factors accumulate, hormone and neurotransmitter balance shifts, and extracellular vesicle (EV) cargo composition changes (Fafian-Labora and O'Loghlen, 2020; López-Otin et al., 2013). These alterations propagate dysfunction across tissues, as seen in heterochronic parabiosis studies where young circulation rejuvenates aged tissues (Conboy and Rando, 2012).

#### 3.2.8.2. LXRs and intercellular communication.
LXRs regulate multiple intercellular signaling circuits. In the endocrine system, they modulate adrenal steroidogenesis (STAR, CYP11A1, HSD3B1) and influence pituitary-adrenal feedback via 11β-HSD1, thereby affecting ACTH and cortisol dynamics (Cummins et al., 2006; Nilsson et al., 2007). In pancreatic β-cells, LXRβ enhances glucose-stimulated insulin secretion
and insulin gene expression, although LXR-driven SREBP1c activation can impair this under lipotoxic conditions (Efanov et al., 2004; Green et al., 2009; Meng et al., 2012; Zitzer et al., 2006). LXR activation in hepatocytes suppresses FGF21, a growth factor implicated in longevity (Uebanso et al., 2012).

LXRs also shape extracellular vesicle (EV) communication. DDA, via LXRβ, reprograms tumor exosomes toward immunogenic cargo enriched in bis(monoacylglycerol)phosphate (BMP), stimulating dendritic cell activation and antitumor immunity. In contrast, oxysterols such as 22 (R)-HC oppose these effects, favoring immune suppression (de Medina et al., 2023b; Record et al., 2022). Moreover, 27-HC released from neutrophils promotes pro-tumoral EV production (Baek et al., 2021).

These findings underscore that LXRs are key modulators of hor-
monal, metabolic, and vesicle-mediated communication. Dysregulation
of these circuits with age suggests that LXR-targeted therapies could
recalibrate systemic signaling, influencing metabolism, immunity, and
tissue homeostasis across multiple organ systems.

3.2.9. LXRs "ecosystem" and hallmarks of aging

Altogether, these findings demonstrate that LXRs influence several hallmarks of aging and may therefore affect both the aging process and the onset and progression of age-related diseases. Most studies to date have employed synthetic LXR ligands (Table 2), whereas endogenous ligands (Fig. 3) are likely to serve as physiological regulators of aging. This underscores the need for deeper investigation into the roles of these endogenous compounds.

It can be anticipated that LXR-dependent modulation of the hallmarks of aging whether inductive, inhibitory, or neutral and its impact on aging and age-related pathologies will be dictated by multiple factors (Fig. 7). These include the nature and abundance of endogenous LXR ligands; the expression levels of co-regulators (coactivators and co-repressors); and the relative abundance of LXR isoforms (LXRα and/or LXRβ). Furthermore, the expression of enzymes involved in the biosynthesis (e.g., CYP46A1, CH25H, DDA synthase, CYP27A1, SULT2B1b, STS) and inactivation (e.g., ACAT1/SOAT1) of endogenous LXR ligands (Chen et al., 2007; Huynh et al., 2024; Segala et al., 2017), as well as that of co-regulators, is highly tissue- and cell type-dependent.

As a result, the transcriptional activity driven by LXRs and

consequently their impact on the hallmarks of aging and age-related disease emerges from a dynamic “LXR ecosystem”, as illustrated in Fig. 7. Exploring how this LXR ecosystem changes with age and how it influences aging hallmarks and related pathologies represents a promising avenue for future research in geroscience.

4. LXR and age-related diseases

4.1. LXR and atherosclerosis

Atherosclerosis arises from the interplay of cholesterol-laden macropathages (foam cells), chronic vascular inflammation, and defective efferocytosis. LXRs are central regulators of these processes across macrophages, endothelial cells, and vascular smooth muscle. Upon activation, LXRs induce ABCA1, ABCG1, and APOE, promoting RCT and reducing foam-cell burden (Calkin and Tontonoz, 2010; Im and Osborne, 2011). In parallel, LXRs repress vascular inflammation via transrepression, cis-repression of inflammatory enhancers, and membrane phospholipid remodeling (Ghisletti et al., 2007; Joseph et al., 2003; Rong et al., 2013; Thomas et al., 2018). LXRs also prevent the formation of necrotic cores within atheromatous plaques by upregulating MerTK, which enhances efferocytosis (Marathe et al., 2006; N et al., 2009).

Endogenous ligands (e.g., 25-HC, 27-HC) promote RCT but may exert context-dependent inflammatory or tumorigenic effects (Jang et al., 2016; Nelson et al., 2013). Synthetic agonists such as TO901317 and GW3965 reduced atherosclerosis in preclinical models but systemic activation of LXRα in the liver leads to triglyceride accumulation and hepatosteatosis (Repa et al., 2000; Schultz et al., 2000). In contrast, LXRβ drives macrophage cholesterol efflux without strong lipogenic effects (Bradley et al., 2007). This isoform dichotomy prompted efforts to design LXRβ-selective agonists, such as LXR-623 and BMS-852927. Despite proof-of-concept in preclinical models, their clinical development was limited by central nervous system toxicity (LXR-623) and dyslipidemia, including elevated triglycerides and LDL cholesterol (BMS-852927) (Katz et al., 2009; Kick et al., 2015; Kick et al., 2016; Kirchgessner et al., 2015; Kirchgessner et al., 2016). Interestingly, DMHCA, a selective LXR modulator and SLiM mimetic of desmosterol,

LXR «ecosystem»

<figure><img src="image_11.png" /><figcaption>Fig. 7. The LXR “ecosystem” involves the cell type and tissue context, the nature and levels of endogenously produced LXR ligands — which depend on the expression of enzymes involved in their synthesis and degradation as well as the expression of LXR subtypes (LXRα and/or LXRβ), coactivators, and corepressors. This “ecosystem” shapes a specific LXR-dependent transcriptional signature that impacts several hallmarks of aging. ACAT: Acyl-CoA:cholesterol acyltransferase; CoA: coactivator; CoR: corepressor; CYP: cytochrome P450; CH25H: cholesterol 25 hydroxylase; DDAS; SQLE: Squalene epoxidase; Sult2B1b: Sulfotransferase 2B1b; STS: Steroid sulfatase.</figcaption></figure>
displays atheroprotective activity without eliciting adverse metabolic effects in a mouse model of atherosclerosis (Kratzer et al., 2009).

Autophagy contributes to atherosclerosis by sustaining cell viability, enhancing cholesterol efflux, and dampening inflammation (Guo et al., 2022; Hassanpour et al., 2019). Extracellular vesicles (EVs) likewise regulate vascular remodeling and inflammatory signaling (Cappucci et al., 2025). Thus, biased agonists such as DDA extend LXR biology beyond lipid metabolism by promoting autophagy and vesicle-mediated communication, thereby linking LXR signaling to hallmarks of aging and vascular repair (Record et al., 2022; Segala et al., 2017).

In summary, LXRs are a double-edged sword in atherosclerosis: they promote vascular protection but also carry the risk of hepatic lipid accumulation. Future therapies must leverage tissue selectivity of SLiMs, isoform selectivity, and biased signaling, to dissociate the protective effects from the deleterious ones.

## 4.2. LXR and diabetes

LXRs regulate glucose metabolism and insulin sensitivity in a tissue-specific manner. In hepatocytes, LXRα activation induces glucose transporters (GLUT1, GLUT4), glycolytic enzymes (HK2, PFK2, LDHA), and gluconeogenic regulators (PEPCK, G6PC), thereby coupling carbohydrate and lipid metabolism (Laffitte et al., 2003; Steffensen and Gustafsson, 2004). In pancreatic β-cells, LXRβ enhances glucose-stimulated insulin secretion (GSIS) and insulin transcription (Efanov et al., 2004; Green et al., 2009; Zitzer et al., 2006), though excessive LXR-driven lipogenesis impairs GSIS under lipotoxic stress (Meng et al., 2012). In adipose and muscle, LXR activation improves insulin sensitivity via cholesterol efflux and adipokine modulation, whereas hepatic lipogenesis exacerbates insulin resistance (Calkin and Tontonoz, 2010). Moreover, LXR agonism also prevents mitochondrial dysfunction and senescence induced by high glucose (Hayashi et al., 2014; Lin et al., 2022).

Pharmacological activation of LXRs with agonists such as TO901317 and GW3965 has been shown to improve glucose tolerance in obese rodents by upregulating glucose transporters (GLUT1, GLUT4), enhancing glycolysis, and suppressing inflammatory cytokines (Laffitte et al., 2003). Interestingly, the endogenous ligand 22(R)-HC restores insulin-stimulated glucose uptake in skeletal muscle, suggesting tissue selective beneficial metabolic effects (Kase et al., 2006; Kase et al., 2007).

Insights from genetic models have clarified the distinct roles of LXR isoforms in metabolic control. LXRβ-deficient mice develop insulin resistance whereas LXRαβ double-knockout mice remain insulin sensitive and display improved metabolic parameters including lower serum glucose, insulin, and hepatic triglyceride levels under both high-fat and high-carbohydrate diets (Korach-Andre et al., 2011). These findings underscore the essential role of LXRβ in maintaining insulin sensitivity and highlight the deleterious contribution of LXRα to diabetes. Accordingly, selective activation of LXRβ represents a promising therapeutic strategy to harness the insulin-sensitizing and anti-inflammatory benefits of LXR signaling while avoiding hepatic lipotoxicity. In parallel, LXR antagonists such as 25-hydroxycholesterol-3-sulfate (25-HC-3S, larsu costerol) have shown efficacy in improving glucose and insulin tolerance while downregulating key lipogenic genes (SREBP-1c, ACC, FAS) in hepatocytes through inhibition of LXR/SREBP-1c signaling (Guillemot-Legris et al., 2016; Xu et al., 2013). Inverse agonists such as SR9243 offer additional metabolic benefits by actively suppressing basal LXR activity. These compounds not only reduce hepatic lipogenesis but also mitigate the Warburg effect and improve mitochondrial respiration (Carpenter et al., 2019). Given that mitochondrial dysfunction is a hallmark of insulin resistance, targeting LXR to preserve mitochondrial homeostasis may represent a valuable therapeutic angle.

Collectively, these findings advocate for next-generation LXR-targeted therapies that prioritize isoform selectivity (favoring LXRβ), inverse agonism/antagonism, or tissue-specific modulation to dissociate

beneficial metabolic and anti-inflammatory effects from adverse hepatic lipid accumulation. Strategies enhancing mitochondrial function or targeting LXR activity in metabolically relevant cell types such as adipocytes, liver, muscle or pancreatic β-cells could further refine therapeutic precision in the context of insulin resistance and type 2 diabetes.

## 4.3. LXR and cancer

### 4.3.1. Cell differentiation and tumor suppression

LXRs regulate tumor cell fate by influencing lipid metabolism, proliferation, and differentiation. Canonical agonists (TO901317, GW3965, 22(R)-HC) suppress proliferation across prostate, breast, colon, and lung cancers via retinoblastoma hypophosphorylation, c-MYC down-regulation, and induction of CDK inhibitors (Fukuchi et al., 2004; Lo Sasso et al., 2013; Vedin et al., 2013). On the other hand, the LXR inverse agonist SR9243 reduces cancer cell viability and induces apoptotic cell death by repressing lipogenesis and Warburg effect in cancer cells (Flaveny et al., 2015). Endogenous biased ligands such as DDA reprogram malignant cells toward differentiation into normal-like cell phenotype, while inducing autophagic cell death in acute myeloid leukemia and melanoma (Bauriaud-Mallet et al., 2019; de Medina et al., 2009; de Medina et al., 2013; Mouchel et al., 2020; Segala et al., 2017; Serhan et al., 2020).

### 4.3.2. Tumor immunity

LXRs shape the tumor microenvironment. They can suppress dendritic cell maturation and migration (Geyeregger et al., 2007; Villablanca et al., 2010), yet also enhance natural killer (NK) cell cytotoxicity via MICA/MICB induction and promote depletion of immunosuppressive myeloid-derived suppressor cells (MDSCs) through APOE (Bilotta et al., 2019; Pencheva et al., 2014). The agonist RGX-104, now in clinical trials, exploits these mechanisms to enhance antitumor immunity (Tavazoie et al., 2018). Inverse agonists such as SR9243 promote Th1 polarization and CD8+ T-cell activity, further restoring antitumor immunity (Carpenter et al., 2019) whereas sulfated oxysterols (25HC-3S, PFM037) LXR antagonists promoted monocyte-DC differentiation, delayed tumor growth and synergized with anti-PD-1 immunotherapy and adoptive T cell therapy (Raccosta et al., 2023). Finally, a biased agonist such as DDA activates antitumor immunity by producing antitumor extracellular vesicles (de Medina et al., 2023b; Record et al., 2022).

### 4.3.3. Extracellular vesicle signaling

LXRs also control tumor exosome biogenesis. DDA, via LXRβ, drives secretion of vesicles enriched in bis(monoacylglycerol)phosphate (BMP) and immunogenic cargo, stimulating dendritic cell maturation and immune activation (de Medina et al., 2023b; Record et al., 2022). By contrast, 27-HC promotes pro-tumoral vesicle release from neutrophils, fueling progression (Baek et al., 2021).

Taken together, LXRs play multifaceted roles in cancer biology: reprogramming tumor cells, modulating immunity, and shaping vesicle-mediated communication. Their context-dependent effects highlight the potential of biased agonists (e.g., DDA) and antagonists/inverse agonists (e.g., SR9243, sulfated oxysterols) to achieve tumor-selective therapeutic outcomes.

## 4.4. LXR and age-related macular degeneration (AMD)

AMD is characterized by lipid- and protein-rich drusen deposits, chronic para-inflammation at the retinal pigment epithelium (RPE)-Bruch's membrane-choriocapillaris complex, and progressive photoreceptor/RPE dysfunction. LXRs, as regulators of cholesterol efflux, phospholipid remodeling, and inflammation, are well-positioned to modulate AMD pathophysiology.

LXR expression in RPE declines with age, while pharmacological activation reduces ocular lipid deposition and inflammation and
improves retinal outcomes in preclinical models (Choudhary et al., 2020). LXR agonists induce ABCA1/ABCG1 and other RCT components, limiting sub-RPE lipid loading that precedes drusen formation. They also remodel phospholipids via LPCAT3 and PCYT2, alleviating ER stress and supporting membrane integrity (Rong et al., 2013; Zhu and Bakovic, 2008).

Anti-inflammatory activity is mediated through canonical LXR transrepression and cis-repression of pro-inflammatory genes (Ghisletti et al., 2007; Joseph et al., 2003; Thomas et al., 2018). LXR activation further supports mitochondrial function and autophagy, processes critical for RPE health and drusen clearance (Chiang et al., 2022; Segala et al., 2017).

However, systemic pan-agonists induce hepatic lipogenesis and hypertriglyceridemia, limiting clinical use. In addition, LXR agonism was associated with reduced NAD+ levels, which trigger mitochondrial dysfunction, macrophage senescence, and the development of subretinal drusenoid deposits in mice (Terao et al., 2024).

Promising strategies for AMD include:

- Tissue-targeted delivery to the eye, minimizing systemic exposure.

- SLiMs to activate efflux, anti-inflammatory pathways, and mitochondrial function without inducing lipogenesis (Bradley et al., 2007; Muse et al., 2018).

- Transrepressing selective ligands to emphasize anti-inflammatory support (Aoyama et al., 2012; Chao et al., 2008; Nomura et al., 2015).

Key gaps remain, including isoform-specific roles in the human retina and identification of physiological LXR ligands in ocular tissues. Nonetheless, preclinical data strongly support LXRs as therapeutic candidates for dry AMD.

## 4.5. LXR and osteoporosis

Osteoporosis, a leading cause of age-related skeletal fragility, results from disrupted balance between bone formation and resorption. LXRs influence both osteoblast and osteoclast biology.

In mesenchymal stem cells, LXRα activation promotes osteoblast differentiation while suppressing adipogenesis via Wnt/β-catenin signaling, suggesting anti-osteoporotic potential (Matsushita et al., 2016). Endogenous ligands such as 20(S)-HC, and 25-HC have also been implicated in osteoblast differentiation and skeletal homeostasis (Che et al., 2022). However, ligand- and context-dependent effects have been reported, with some agonists impairing osteoblast maturation (Zaidi et al., 2023).

Osteoclastogenesis is also regulated by LXRs. Synthetic agonists (TO901317, GW3965) suppress osteoclast precursor fusion by inducing cholesterol efflux genes (ABCA1, ABCG1), thereby reducing bone resorption and increasing bone mass in mouse models (Cao et al., 2013; Kleyer et al., 2012). More specifically, osteoclastogenesis is selectively regulated by LXRβ: genetic deletion of LXRβ, but not LXRα, promotes osteoclast differentiation (Remen et al., 2011), whereas LXRβ-selective agonists, such as spiro[pyrrolidine-3,3'-oxindole] derivatives, inhibit RANKL-induced osteoclast formation and bone resorption by enhancing cholesterol efflux via ABCA1/ABCG1, thereby increasing bone mass in vitro and in vivo (Chen et al., 2023).

Inflammatory cytokines (TNFα, IL-6) exacerbate bone loss with aging. LXR agonists dampen these cytokines by repressing NF-κB/AP-1 pathways, indirectly protecting bone (Ghisletti et al., 2007; Joseph et al., 2003). 27-HC in postmenopausal women have been suggested to act as a selective estrogen receptor modulator (SERM) and LXR modulator, impairing bone mass (Nelson et al., 2011).

Overall, LXRs integrate metabolic, inflammatory, and lineage signals that directly shape bone turnover. Selective LXRβ agonists and SLiMs may therefore represent future therapeutic options for osteoporosis, provided systemic lipogenic effects are avoided.

## 4.6. LXR and neurodegenerative diseases

LXRs are widely expressed in neurons, astrocytes, oligodendrocytes, and microglia, where they regulate cholesterol homeostasis, neuroinflammation, and synaptic function. Their dysregulation contributes to major age-related neurological disorders.

### 4.6.1. Alzheimer's disease (AD)

LXR agonists (TO901317, GW3965, DMHCA, 22(R)-HC) reduce β-amyloid burden in AD models by enhancing ABCA1/APOE-mediated efflux, improving amyloid clearance (Courtney and Landreth, 2016; Wang et al., 2025; Zhang et al., 2024). GW3965 also rescues synaptic gene expression and cognition through epigenetic remodeling (Sandoval-Hernandez et al., 2016a; Sandoval-Hernandez et al., 2016b). LXR agonism protects mitochondria against β-amyloid-induced damage (Chiang et al., 2022).

### 4.6.2. Parkinson's disease (PD)

In toxin-induced PD models, GW3965 preserves dopaminergic neurons, while 22(R)-HC promotes dopaminergic differentiation from progenitors (Dai et al., 2012; Singh et al., 2021). These effects suggest both neuroprotective and regenerative roles.

### 4.6.3. Presbycusis (age-related hearing loss)

LXRβ⁻/⁻ mice display hallmark cochlear degeneration (spiral ganglion neuron loss, macrophage activation, demyelination, reduced glutamine synthetase, glutamate accumulation), paralleling presbycusis pathology (Song et al., 2022b). The biased ligand DDA improves auditory sensitivity and cochlear responses in vivo, via a probable LXRβ-driven metabolic reprogramming (Fransson et al., 2015).

### 4.6.4. Stroke

LXR agonists reduce infarct size and enhance blood-brain barrier integrity via anti-inflammatory and efflux pathways, while also supporting angiogenesis and tissue repair (Cui et al., 2017; Im and Osborne, 2011).

Other neurological disorders: In multiple sclerosis, LXR agonists reduce demyelination, and LXRβ deficiency has been linked to motor neuron degeneration resembling amyotrophic lateral sclerosis (ALS), implicating LXRs in oligodendrocyte and motor neuron survival (Cui et al., 2017; Song et al., 2022a).

Taken together, LXRs act as neuroprotective hubs by regulating cholesterol trafficking, inflammation, mitochondrial function, and epigenetics. While pan-agonists show efficacy in models, translation will require CNS-targeted LXRβ selective agonists or SLiMs with improved safety.

## 5. General conclusion

Liver X receptors emerge as central transcriptional hubs that integrate lipid metabolism, inflammation, autophagy, mitochondrial homeostasis, stem cell fate, and intercellular communication. By intersecting with nearly all the recognized hallmarks of aging genomic instability, epigenetics, nutrient sensing, mitochondrial function, senescence, stem cell exhaustion, and inflamming LXRs extend far beyond their canonical role as cholesterol sensors.

Preclinical studies have demonstrated that LXR modulation can delay or attenuate multiple age-related pathologies: atherosclerosis through enhanced cholesterol efflux and efferocytosis; diabetes via improved insulin sensitivity and glucose handling; cancer through tumor redifferentiation, immunomodulation, and biased extracellular vesicle signaling; AMD by restoring lipid homeostasis and dampening para-inflammation; osteoporosis by balancing osteoblast and osteoclast activity; and neurodegeneration through cholesterol trafficking, synaptic protection, and regenerative support. These wide-ranging effects suggest that LXR-targeted therapies could be developed either as
disease-specific interventions or as geroscience-guided therapeutics designed to address multiple disorders simultaneously (Fig. 8).

However, translation to the clinic has been hindered by the lipogenic liabilities of pan-agonists, especially those that engage LXRα in hepatocytes. To avoid these side effects, LXRβ-selective agonists were developed as a more targeted approach. These agonists show promise in treating multiple age-related pathologies, including atherosclerosis, neurodegeneration, diabetes, and cancer. However, clinical experience has revealed several challenges. For example, LXR-623 caused unexpected central nervous system (CNS) adverse effects, such as altered perception and paranoia, while XL041 demonstrated efficacy in preclinical models but was associated with hypertriglyceridemia and elevated low-density lipoprotein (LDL) in humans.

Looking forward, the path to clinical utility will require a new generation of pharmacological strategies:

- Isoform-selective ligands that exploit LXRβ for vascular and neuroprotective effects while sparing LXRα-driven lipogenesis.

- Selective LXR modulators (SLiMs) that bias transcription toward cholesterol efflux, mitochondrial health, cell differentiation, or anti-inflammatory programs, depending on tissue context and therapeutic application.

- Inverse agonists to suppress hepatic lipogenesis and the Warburg effect, with applications in fatty liver disease, diabetes and cancer.

- Biased agonists such as dendrogenin A that counteract some hallmarks of aging such as autophagy, cell differentiation and intercellular communication.

Interestingly, nature provides ligands with remarkable properties, including: SLiMs such as desmosterol, which activate cholesterol efflux without inducing deleterious lipogenesis; 25-HC-3S, an antagonist with therapeutic potential for liver steatosis and diabetes; and DDA, a biased agonist that induces non-canonical LXR-dependent processes (autophagy and sEV production) and displays potent antitumor, pro-differentiation, and neurotrophic activities.

Endogenous LXR ligands represent a growing family of naturally occurring metabolites, and a large variety of LXR-targeting metabolites remain to be discovered. Consequently, “nature mimicry” constitutes a promising approach for the development of novel therapeutics targeting LXRs.

From a geroscience perspective, LXRs are in a unique position to modulate multiple hallmarks simultaneously, offering the potential for broad-spectrum gerotherapeutics. Such strategies may ultimately shift clinical practice from disease-specific management to healthspan extension, delaying the onset of cardiovascular disease, diabetes, neurodegeneration, osteoporosis, and sensory decline in parallel.

In conclusion, LXRs should be regarded not only as cholesterol regulators but as systemic guardians of resilience. The next phase of research must focus on refining pharmacological selectivity and delivery, while leveraging insights from endogenous ligands. Unlocking their therapeutic potential could catalyze a paradigm shift in medicine where targeting LXRs contributes not just to treating individual conditions, but to extending healthy aging across the human lifespan.

### CRediT authorship contribution statement

**Marc Poirot:** Conceptualization, Writing – original draft, **Julio Buñay:** Writing – review & editing, **Silia Ayadi:** Writing – review & editing, **Sandrine Silvente-Poirot:** Writing – review & editing, **Philippe de Medina:** Conceptualization, Writing – original draft. All authors read and approve the final version of the manuscript.

<figure><img src="image_12.png" /><figcaption>**Fig. 8.** LXR-regulated age-related diseases and ligand-based therapeutic strategies.</figcaption></figure>

### Declaration of Generative AI and AI-assisted technologies in the writing process

During the preparation of this work, the authors used ChatGPT (OpenAI) to improve the clarity and readability of the manuscript. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article.

### Declaration of Competing Interest

The authors declare no competing financial interests.

### Acknowledgements

This work was funded by an internal grant from the “Institut National de la Santé et de la Recherche Médicale”, the “Université de Toulouse”, the Association pour la Recherche sur le Cancer (DASYNT3, ANR-24-CE44-4332), the Institut National du Cancer (PLBIO2020-028 and PLBIO2023-050), the World Cancer Research Fund International and the charities ELLES, J'Y V, Orange Care and URAFIKI JUU. The team is a member of the French Network for Nutrition And Cancer Research (NACRe network) and of the European Network for Oxysterol Research (ENOR).

### References

- Abokyi, S., Ghartery-Kwansah, G., Tse, D.Y., 2023. TFEB is a central regulator of the aging process and age-related diseases. Ageing Res. Rev. 89, 101985.

- Albers, M., Blume, B., Schlueter, T., Wright, M.B., Kober, I., Kremoser, C., Deuschle, U., Koegl, M., 2006. A novel principle for partial agonism of liver X receptor ligands. Compét. Recruit. Act. Repressors. J. Biol. Chem. 281, 4920–4930.

- Antebi, A., 2015. Nuclear receptor signal transduction in C. elegans. WormBook 1-49.

- Aoyama, A., Endo-Umeda, K., Kishida, K., Ohgane, K., Noguchi-Yachide, T., Aoyama, H., Ishikawa, M., Miyachi, H., Makishima, M., Hashimoto, Y., 2012. Design, synthesis, and biological evaluation of novel transrepression-selective liver X receptor (LXR) ligands with 5,11-dihydro-5-methyl-11-methylene-6H-dibenz[b,e]azepin-6-one skeleton. J. Med. Chem. 55, 7360–7377.

- Asquith, D.L., Miller, A.M., Hueber, A.J., McKinnon, H.J., Sattar, N., Graham, G.J., McInnes, I.B., 2009. Liver X receptor agonism promotes articular inflammation in murine collagen-induced arthritis. Arthritis Rheum. 60, 2655–2665.
Baechle, J.J., Chen, N., Makhijani, P., Winer, S., Furman, D., Winer, D.A., 2023. Chronic inflammation and the hallmarks of aging. Mol. Metab. 74, 101755.

Baek, A.E., Krawczynska, N., Das Gupta, A., Dvoretskiy, S.V., You, S., Park, J., Deng, Y.-H., Sorrells, J.E., Smith, B.P., Ma, L., Nelson, A.T., McDowell, H.B., Sprenger, A., Henn, M.A., Madak-Erdogan, Z., Kong, H., Boppart, S.A., Boppart, M.D., Nelson, E. R., 2021. The cholesterol metabolite 27HC increases secretion of extracellular vesicles which promote breast cancer progression. Endocrinology 162, bqbab095.

Bannister, A.J., Kouzarides, T., 2011. Regulation of chromatin by histone modifications. Cell Res. 21, 381-395.

Bapteste, E., Huneman, P., Keller, L., Teuliere, J., Lopez, P., Teeling, E.C., Lindner, A.B., Baudisch, A., Ludington, W.B., Franceschi, C., 2023. Expanding evolutionary theories of ageing to better account for symbioses and interactions throughout the Web of Life. Ageing Res. Rev. 89, 101982.

Barardo, D., Thornton, D., Thoppil, H., Walsh, M., Sharifi, S., Ferreira, S., Anžić, A., Fernandes, M., Monteiro, P., Grum, T., Cordeiro, R., De-Souza, E.A., Budovsky, A., Araujo, N., Gruber, J., Petrascheck, M., Fraifeld, V.E., Zhavoronkov, A., Moskalev, A., de Magalhães, J.P., 2017. The DrugAge database of aging-related drugs. Aging Cell 16, 594-597.

Barzilai, N., 2003. Unique lipoprotein phenotype and genotype associated with exceptional longevity. JAMA 290, 2030.
Bauriaud-Mallet, M., Vija-Racaru, L., Brillouet, S., Mallinger, A., de Medina, P., Rives, A., Payre, B., Poirot, M., Courbon, F., Silente-Poirot, S., 2019. The cholesterol-derived metabolite dendrogenin A functionally reprograms breast adenocarcinoma and undifferentiated thyroid cancer cells. J. Steroid Biochem. Mol. Biol. 192, 105390.

Behrens, A., van Deursen, J.M., Rudolph, K.L., Schumacher, B., 2014. Impact of genomic damage and aging on stem cell function. Nat. Cell Biol. 16, 201-207.

Bell, C.G., Lowe, R., Adams, P.D., Baccarelli, A.A., Beck, S., Bell, J.T., Christensen, B.C., Gladyshev, V.N., Heijmans, B.T., Horvath, S., Ideker, T., Issa, J.J., Kelsey, K.T., Marioni, R.E., Reik, W., Repton, C.L., Schalkwyk, L.C., Teschendorff, A.E., Wagner, W., Zhang, K., Rakyan, V.K., 2019. DNA methylation aging clocks: challenges and recommendations. Genome Biol. 20, 249.

Belorusova, A.Y., Evertsson, E., Hovdal, D., Sandmark, J., Bratt, E., Maxvall, I., Schulman, I.G., Akerblad, P., Lindstedt, E.L., 2019. Structural analysis identifies an escape route from the adverse lipogenic effects of liver X receptor ligands. Commun. Biol. 2, 431.

Berrodin, T.J., Shen, Q., Quinet, E.M., Yudt, M.R., Freedman, L.P., Nagpal, S., 2010. Identification of Salpha, galpha-epoxysterol as a novel modulator of liver X receptor activity. Mol. Pharm. 78, 1046-1058.

Biga, P.R., Duan, J.E., Young, T.E., Marks, J.R., Bronikowski, A., Decena, L.P., Randolph, E.C., Pavuluri, A.G., Li, G., Fang, Y., Wilkinson, G.S., Singh, G., Nigrin, N. T., Larschan, E.N., Lonski, A.J., Riddle, N.C., Consortium, I., 2025. Hallmarks of aging: a user's guide for comparative biologists. Ageing Res. 104, 102616.

Bilotta, M.T., Abruzzese, M.P., Molfetta, R., Scarno, G., Fionda, C., Zingoni, A., Soriani, A., Garofalo, T., Petrucci, M.T., Ricciardi, M.R., Paolini, R., Santoni, A., Cippitelli, M., 2019. Activation of liver X receptor up-regulates the expression of the NKG2D ligands MICA and MICB in multiple myeloma through different molecular mechanisms. FASEB J. 33, 9489-9504.

Bischoff, E.D., Daige, C.L., Petrowski, M., Dedman, H., Pattison, J., Juliano, J., Li, A.C., Schulman, I.G., 2010. Non-redundant roles for LXRalpha and LXRbeta in atherosclerosis susceptibility in low density lipoprotein receptor knockout mice. J. Lipid Res. 51, 900-906.

Boergesen, M., Pedersen, T.A., Gross, B., van Heeringen, S.J., Hagenbeek, D., Bindesboll, C., Caron, S., Lalloyer, F., Steffensen, K.R., Nebb, H.I., Gustafsson, J.A., Stunnenberg, H.G., Staels, B., Mandrup, S., 2012. Genome-wide profiling of liver X receptor, retinoid X receptor, and peroxisome proliferator-activated receptor alpha in mouse liver reveals extensive sharing of binding sites. Mol. Cell Biol. 32, 852-867.

Bradley, M.N., Hong, C., Chen, M., Joseph, S.B., Wilpitz, D.C., Wang, X., Lusis, A.J., Collins, A., Hseuh, W.A., Collins, J.L., Tangirala, R.K., Tontonoz, P., 2007. Ligand activation of LXR beta reverses atherosclerosis and cellular cholesterol overload in mice lacking LXR alpha and apoE. J. Clin. Invest. 117, 2337-2346.

Burris, T.P., de Vera, I.M.S., Cote, I., Flaveny, C.A., Wanninayake, U.S., Chatterjee, A., Walker, J.K., Steinauer, N., Zhang, J., Coons, L.A., Korach, K.S., Cain, D.W., Hollenberg, A.N., Webb, P., Forrest, D., Jetten, A.M., Edwards, D.P., Grimm, S.L., Hartig, S., Lange, C.A., Richer, J.K., Sartorius, C.A., Tetel, M., Billon, C., Elgenty, B., Hegazy, L., Griffett, K., Peinetti, N., Burnstein, K.L., Hughes, T.S., Sitaula, S., Stayrook, K.R., Culver, A., Murray, M.H., Finck, B.N., Cidlowski, J.A., 2023. International union of basic and clinical pharmacology cxiii: nuclear receptor superfamily-update 2023. Pharm. Rev. 75, 1233-1318.

Cai, Y., Tang, X., Chen, X., Li, X., Wang, Y., Bao, X., Wang, L., Sun, D., Zhao, J., Xing, Y., Warner, M., Xu, H., Gustafsson, J.A., Fan, X., 2018. Liver X receptor beta regulates the development of the dentate gyrus and autistic-like behavior in the mouse. Proc. Natl. Acad. Sci. USA 115, E2725-E2733.

Calkin, A.C., Tontonoz, P., 2010. Liver X receptor signaling pathways and atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 30, 1513-1518.

Cao, H., Zhu, K., Qiu, L., Li, S., Niu, H., Hao, M., Yang, S., Zhao, Z., Lai, Y., Anderson, J. L., Fan, J., Im, H.J., Chen, D., Roodman, G.D., Xiao, G., 2013. Critical role of AKT protein in myeloma-induced osteoclast formation and osteolysis. J. Biol. Chem. 288, 30399-30410.

Cappucci, I.P., Tremoli, E., Zavan, B., Ferroni, L., 2025. Circulating extracellular vesicles in cardiovascular disease. Int. J. Mol. Sci. 26.

Carpenter, K.J., Valfort, A.C., Steinauer, N., Chatterjee, A., Abuirqeba, S., Majidi, S., Sengupta, M., Di Paolo, R.J., Shornick, L.P., Zhang, J., Flaveny, C.A., 2019. LXR- inverse agonism stimulates immune-mediated tumor destruction by enhancing CD8 T-cell activity in triple negative breast cancer. Sci. Rep. 9, 19530.

Castrillo, A., Joseph, S.B., Vaidya, S.A., Haberland, M., Fogelman, A.M., Cheng, G., Tontonoz, P., 2003. Crosstalk between LXR and toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism. Mol. Cell 12, 805-816.

Chang, K.C., Shen, Q., Oh, I.G., Jelinsky, S.A., Jenkins, S.F., Wang, W., Wang, Y., LaCava, M., Yudt, M.R., Thompson, C.C., Freedman, L.P., Chung, J.H., Nagpal, S., 2008. Liver X receptor is a therapeutic target for photoaging and chronological skin aging. Mol. Endocrinol. 22, 2407-2419.

Chao, E.Y., Caravella, J.A., Watson, M.A., Campobasso, N., Ghisletti, S., Billin, A.N., Galardi, C., Wang, P., Laffitte, B.A., Iannone, M.A., Goodwin, B.J., Nichols, J.A., Parks, D.J., Stewart, E., Wiethe, R.W., Williams, S.P., Smallwood, A., Pearce, K.H., Glass, C.K., Willson, T.M., Zuercher, W.J., Collins, J.L., 2008. Structure-guided design of N-phenyl tertiary amines as transrepression-selective liver X receptor modulators with anti-inflammatory activity. J. Med. Chem. 51, 5758-5765.

Che, Y., Yang, J., Tang, F., Wei, Z., Chao, Y., Li, N., Li, H., Wu, S., Dong, X., 2022. New Function of Cholesterol Oxidation Products Involved in Osteoporosis Pathogenesis. Int J. Mol. Sci. 23.

Chen, H., Hua, P., Huang, D., Zhang, Y., Zhou, H., Xu, J., Gu, Q., 2023. Discovery of Spiro [pyrrolidine-3,3'-oxindole] LXRbeta agonists for the treatment of osteoporosis. J. Med. Chem. 66, 752-765.

Chen, W., Chen, G., Head, D.L., Mangelsdorf, D.J., Russell, D.W., 2007. Enzymatic reduction of oxysterols impairs LXR signaling in cultured cells and the livers of mice. Cell Metab. 5, 73-79.

Chen, Z., Chen, H., Zhang, Z., Ding, P., Yan, X., Li, Y., Zhang, S., Gu, Q., Zhou, H., Xu, J., 2020. Discovery of novel liver X receptor inverse agonists as lipogenesis inhibitors. Eur. J. Med. Chem. 206, 112793.

Chiang, M.C., Nicol, C.J.B., Chen, S.J., Huang, R.N., 2022. T0901317 activation of LXR-dependent pathways mitigate amyloid-beta peptide-induced neurotoxicity in 3D human neural stem cell culture scaffolds and AD mice. Brain Res. Bull. 178, 57-68.

Choudhary, M., Ismail, E.N., Yao, P.L., Tayyari, F., Radu, R.A., Nusinowitz, S., Boulton, M.E., Apte, R.S., Ruberti, J.W., Handa, J.T., Tontonoz, P., Malek, G., 2020. LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target. JCI Insight 5.

Cole, J.J., Robertson, N.A., Rather, M.I., Thomson, J.P., McBryan, T., Sproul, D., Wang, T., Brock, C., Clark, W., Ideker, T., Meehan, R.R., Taylor, M.A., Brown-Borg, H. M., Adams, P.D., 2017. Diverse interventions that extend mouse lifespan suppress shared age-associated epigenetic changes at critical gene regulatory regions. Genome Biol. 18, 58-61.

Collaborators, G.B.D.Co.D., 2018. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study. Lancet 392, 1736-1788.

Conboy, I.M., Rando, T.A., 2012. Heterochronic parabiosis for the study of the effects of aging on stem cells and their niches. Cell Cycle 11, 2260-2267.

Cook, I., Leyh, T.S., 2023. Sulfotransferase 2B1b, sterol sulfonation, and disease. Pharm. Rev. 75, 521-531.

Coppé, J.-P., Desprez, P.-Y., Krtolica, A., Campisi, J., 2010. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. Mech. Dis. 5, 99-118.

Courtney, R., Landreth, G.E., 2016. LXR regulation of brain cholesterol: from development to disease. Trends Endocrinol. Metab. 27, 404-414.

Cui, X., Chopp, M., Zhang, Z., Li, R., Zacharek, A., Landschoot-Ward, J., Venkat, P., Chen, J., 2017. ABCA1/ApoE/HDL pathway mediates GW3965-induced neurorestoration after stroke. Stroke 48, 459-467.

Cummins, C.L., Volle, D.H., Zhang, Y., McDonald, J.G., Sion, B., Lefrancois-Martinez, A. M., Caira, F., Veyszire, G., Mangelsdorf, D.J., Lobaccaro, J.M., 2006. Liver X receptors regulate adrenal cholesterol balance. J. Clin. Invest. 116, 1902-1912.

Czarnowicki, T., Dohlman, A.B., Malik, K., Antonini, D., Bissonnette, R., Chan, T.C., Zhou, L., Wen, H.C., Estrada, Y., Xu, H., Bryson, C., Shen, J., Lala, D., Ma'ayan, A., McGeehan, G., Gregg, R., Guttman-Yassky, E., 2018. Effect of short-term liver X receptor activation on epidermal barrier features in mild to moderate atopic dermatitis: a randomized controlled trial. Ann. Allergy Asthma Immunol. 120, 631-640 e611.

Dai, Y.B., Tan, X.J., Wu, W.F., Warner, M., Gustafsson, J.A., 2012. Liver X receptor beta protects dopaminergic neurons in a mouse model of Parkinson disease. Proc. Natl. Acad. Sci. USA 109, 13112-13117.

Dallel, S., Tauveron, I., Brugnon, F., Baron, S., Lobaccaro, J.M.A., Maqdasy, S., 2018. Liver X receptors: a possible link between lipid disorders and female infertility. Int J. Mol. Sci. 19.

Das, S., Parigi, S.M., Luo, X., Fransson, J., Kern, B.C., Okhovat, A., Diaz, O.E., Sorini, C., Czarnewski, P., Webb, A.T., Morales, R.A., Lebon, C., Monasterio, G., Castillo, F., Tripathi, K.P., He, N., Pelczar, P., Schaltenberg, N., De la Fuente, M., Lopez-Kostner, F., Nylen, S., Larsen, H.L., Kuiper, R., Antonson, P., Hermoso, M.A., Huber, S., Biton, M., Scharaw, S., Gustafsson, J.A., Katajisto, P., Villablanca, E.J., 2025. Liver X receptor unlinks intestinal regeneration and tumorigenesis. Nature 637, 1198-1206.

Dasgupta, S., Lonard, D.M., O'Malley, B.W., 2014. Nuclear receptor coactivators: master regulators of human health and disease. Annu. Rev. Med. 65, 279-292.

DeBalsi, K.L., Hoff, K.E., Copeland, W.C., 2017. Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases. Ageing Res. Rev. 33, 89-104.

Efanov, A.M., Sewing, S., Bokvist, K., Gromada, J., 2004. Liver X receptor activation stimulates insulin secretion via modulation of glucose and lipid metabolism in pancreatic beta-cells. Diabetes 53 (3), S75-S78.

Elgenty, B., Griffett, K., Hegazy, L., Di Fruscia, P., Sample, K., Schoepke, E., Kamenecka, T.M., Burris, T.P., 2022. Synthesis and structure activity relationship of the first class of LXR inverse agonists. Bioorg. Chem. 119, 105540.
El-Gendy, B.E.M., Goher, S.S., Hegazy, L.S., Arief, M.M.H., Burris, T.P., 2018. Recent advances in the medicinal chemistry of liver X receptors. J. Med Chem. 61, 10935-10956.

van Exel, E., Koopman, J.J.E., Bodegom, D.V., Meij, J.J., Knijff, P., Ziem, J.B., Finch, C. E., Westendorp, R.G.J., 2017. Effect of APOE epsilon 4 allele on survival and fertility in an adverse environment. PLoS One 12, e0179497.

Fafian-Labora, J.A., O'Loghlen, A., 2020. Classical and nonclassical intercellular communication in senescence and ageing. Trends Cell Biol. 30, 628-639.

Fessler, M.B., 2018. The challenges and promise of targeting the Liver X Receptors for treatment of inflammatory disease. Pharm. Ther. 181, 1-12.

Flaveny, C.A., Griffet, K., El-Gendy Bel, D., Kazantzis, M., Sengupta, M., Amelio, A.L., Chatterjee, A., Walker, J., Solit, L.A., Kamelecka, T.M., Burris, T.P., 2015. Broad anti-tumor activity of a small molecule that selectively targets the warburg effect and lipogenesis. Cancer Cell 28, 42-56.

Fontaine, C., Rigamonti, E., Nohara, A., Gervois, P., Teissier, E., Fruchart, J.C., Staels, B., Chinieta-Gbaguidi, G., 2007. Liver X receptor activation potentiates the lipopolysaccharide response in human macrophages. Circ. Res 101, 40-49.

Franceschi, C., Campisi, J., 2014. Chronic inflammation (inflammating) and its potential contribution to age-associated diseases. J. Gerontol. A Biol. Sci. Med Sci. 69 (1), S4-S9.

Franceschi, C., Garagnani, P., Parini, P., Giuliani, C., Santoro, A., 2018b. Inflammating: a new immune-metabolic viewpoint for age-related diseases. Nat. Rev. Endocrinol. 14, 576-590.

Franceschi, C., Garagnani, P., Morsiani, C., Conte, M., Santoro, A., Grignolio, A., Monti, D., Capri, M., Salvioli, S., 2018a. The continuum of aging and age-related diseases: common mechanisms but different rates. Front. Med. 5, 61.

Fransson, A., de Medina, P., Paillasse, M.R., Silvente-Poirot, S., Poirot, M., Ulfendahl, M., 2015. Dendrogenin A and B two new steroidal alkaloids increasing neural responsiveness in the deafened guinea pig. Front. Aging Neurosci. 7.

Fukuchi, J., Kokontis, J.M., Hiipakka, R.A., Chuu, C.P., Liao, S., 2004. Antiproliferative effect of liver X receptor agonists on LNCaP human prostate cancer cells. Cancer Res. 64, 7686-7689.

Garatachea, N., Emanuele, E., Calero, M., Fuku, N., Arai, Y., Abe, Y., Murakami, H., Miyachi, M., Yvert, T., Verde, Z., Zea, M.A., Venturini, L., Santiago, C., Santos-Lozano, A., Rodríguez-Romo, G., Ricevuti, G., Hirose, N., Rábano, A., Lucia, A., 2014. ApoE gene and exceptional longevity: Insights from three independent cohorts. Exp. Gerontol. 53, 16-23.

Ge, Y., Zhou, M., Chen, C., Wu, X., Wang, X., 2022. Role of AMPK mediated pathways in autophagy and aging. Biochimie 195, 100-113.

Gerisch, B., Rottiers, V., Li, D., Motola, D.L., Cummins, C.L., Lehrach, H., Mangelsdorf, D. J., Antebi, A., 2007. A bile acid-like steroid modulates Caenorhabditis elegans lifespan through nuclear receptor signaling. Proc. Natl. Acad. Sci. U.S.A. 104, 5014-5019.

Geyeregger, R., Zeyda, M., Bauer, W., Kriehuber, E., Saemann, M.D., Zlabininger, G.J., Maurer, D., Stulnig, T.M., 2007. Liver X receptors regulate dendritic cell phenotype and function through blocked induction of the actin-bundling protein fascin. Blood 109, 4288-4295.

Ghisletti, S., Huang, W., Ogawa, S., Pascual, G., Lin, M.E., Willson, T.M., Rosenfeld, M.G., Glass, C.K., 2007. Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARgamma. Mol. Cell 25, 57-70.

Goldberg, A.D., Allis, C.D., Bernstein, E., 2007. Epigenetics: a landscape takes shape. Cell 128, 635-638.

Gong, H., Guo, P., Zhai, Y., Zhou, J., Uppal, H., Jarzynka, M.J., Song, W.C., Cheng, S.Y., Xie, W., 2007. Estrogen deprivation and inhibition of breast cancer growth in vivo through activation of the orphan nuclear receptor liver X receptor. Mol. Endocrinol. 21, 1781-1790.

Gonzalez-Freire, M., de Cabo, R., Bernier, M., Sollott, S.J., Fabbri, E., Navas, P., Ferrucci, L., 2015. Considering the role of mitochondria in aging. J. Gerontol. A Biol. Sci. Med Sci. 70, 1334-1342.

A-Gonzalez, N., Bensinger, S.J., Hong, C., Beceiro, S., Bradley, M.N., Zelcer, N., Deniz, J., Ramirez, C., Díaz, M., Gallardo, G., Ruiz de Galarreta, C., Salazar, J., Lopez, F., Edwards, P., Parks, J., Andujar, M., Tontonoz, P., Castrillo, A., 2009. Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity 31, 245-258. https://doi.org/10.1016/j.immuni.2009.06.018.

Goodell, M.A., Rando, T.A., 2015. Stem cells and healthy aging. Science 350, 1199-1204.

Green, C.D., Jump, D.B., Olson, L.K., 2009. Elevated insulin secretion from liver X receptor-activated pancreatic beta-cells involves increased de novo lipid synthesis and triacylglyceride turnover. Endocrinology 150, 2637-2645.

Griffett, K., Solt, L.A., El-Gendy Bel, D., Kamenecka, T.M., Burris, T.P., 2013. A liver-selective LXR inverse agonist that suppresses hepatic steatosis. ACS Chem. Biol. 8, 559-567.

Guarente, L., Sinclair, D.A., Kroemer, G., 2024. Human trials exploring anti-aging medicines. Cell Metab. 36, 354-376.

Guillemot-Legris, O., Mutemberezi, V., Muccioli, G.G., 2016. Oxysterols in metabolic syndrome: from bystander molecules to bioactive lipids. Trends Mol. Sci. 22, 594-614.

Guillemot-Legris, O., Muccioli, G.G., 2021. The oxysterome and its receptors as pharmacological targets in inflammatory diseases. Br. J. Pharm., bph.15479

Guo, H., Wei, D., Liu, R., Zhang, C., Jiang, S., Wang, W., Hu, H., Shen, L., Liang, X., 2022. A novel therapeutic strategy for atherosclerosis: autophagy-dependent cholesterol efflux. J. Physiol. Biochem. 78, 557-572.

Hassanein, T., McClain, C.J., Vatsalya, V., Stein, L.L., Flamm, S.L., Martin, P., Cave, M.C., Mitchell Jr., M., Barton, B., Nagy, L., Szabo, G., McCullough, A., Dasarathy, S., Shah, J., Blevins, C., Scott, D., Krebs, W., Brown, J.E., Lin, W., 2024. Safety, pharmacokinetics, and efficacy signals of larsucosterol (DUR-928) in alcohol-associated hepatitis. Am. J. Gastroenterol. 119, 107-115.

Hassanpour, M., Rahbarghazi, R., Nouri, M., Aghamohammadzadeh, N., Safaei, N., Ahmadi, M., 2019. Role of autophagy in atherosclerosis: foe or friend? J. Inflamm. (Lond.) 16, 1-8.

Hayashi, T., Kotani, H., Yamaguchi, T., Taguchi, K., Iida, M., Ina, K., Maeda, M., Kuzuya, M., Hattori, Y., Ignarro, L.J., 2014. Endothelial cellular senescence is inhibited by liver X receptor activation with an additional mechanism for its atheroprotection in diabetes. Proc. Natl. Acad. Sci. U.S.A. 111, 1168-1173.

Hoang, M.H., Jia, Y., Jun, H.J., Lee, J.H., Hwang, K.Y., Choi, D.W., Um, S.J., Lee, B.Y., You, S.G., Lee, S.J., 2012. Taurine is a liver X receptor-alpha ligand and activates transcription of key genes in the reverse cholesterol transport without inducing hepatic lipogenesis. Mol. Nutr. Food Res. 56, 900-911.

Hong, C., Tontonoz, P., 2014. Liver X receptors in lipid metabolism: opportunities for drug discovery. Nat. Rev. Drug Discov. 13, 433-444.

Hou, Y., Wang, Z., Liu, P., Wei, X., Zhang, Z., Fan, S., Zhang, L., Han, F., Song, Y., Chu, L., Zhang, C., 2023. SMPDL3A is a cGAMP-degrading enzyme induced by LXR-mediated lipid metabolism to restrict cGAS-STING DNA sensing. Immunity 55, 2492-2507 e2410.

Huynh, T.N., Havrda, M.C., Zanazzi, G.J., Chang, C.C.Y., Chang, T.Y., 2024. Inhibiting the cholesterol storage enzyme ACAT1/SOAT1 in myelin debris-treated microglial cell lines activates the gene expression of cholesterol efflux transporter ABCA1. Biomolecules 14.

Im, S.S., Osborne, T.F., 2011. Liver x receptors in atherosclerosis and inflammation. Circ. Res. 108, 996-1001.

Jakobsson, T., Venteclef, N., Toresson, G., Damdimopoulos, A.E., Ehrlund, A., Lou, X., Sanyal, S., Steffensen, K.R., Gustafsson, J.A., Treuter, E., 2009. GPS2 is required for cholesterol efflux by triggering histone demethylation, LXR recruitment, and coregulator assembly at the ABCG1 locus. Mol. Cell 34, 510-518.

Jang, J., Park, S., Jin Hur, H., Cho, H.J., Hwang, I., Pyo Kang, Y., Im, I., Lee, H., Lee, E., Yang, W., Kang, H.C., Won Kwon, S., Yu, J.W., Kim, D.W., 2016. 25-hydroxycholesterol contributes to cerebral inflammation of X-linked adrenoleukodystrophy through activation of the NLRP3 inflammasome. Nat. Commun. 7, 13129.

Janowski, B.A., Willy, P.J., Devi, T.R., Falck, J.R., Mangelsdorf, D.J., 1996. An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature 383, 728-731.

Janowski, B.A., Grogan, M.J., Jones, S.A., Wisely, G.B., Kliewer, S.A., Corey, E.J., Mangelsdorf, D.J., 1999. Structural requirements of ligands for the oxysterol liver X receptors LXR and LXR. Proc. Natl. Acad. Sci. U.S.A. 96, 266-271.

Jiang, Y.J., Kim, P., Elias, P.M., Feingold, K.R., 2005. LXR and PPAR activators stimulate cholesterol sulfotransferase type 2 isoform 1b in human keratinocytes. J. Lipid Res. 46, 2657-2666.

Joseph, S.B., Castrillo, A., Laffitte, B.A., Mangelsdorf, D.J., Tontonoz, P., 2003. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat. Med. 9, 213-219.

Kase, E.T., Andersen, B., Nebb, H.I., Rustan, A.C., Thoresen, G.H., 2006. 22-Hydroxycholesterols regulate lipid metabolism differently than T0901317 in human myotubes. Biochim. Biophys. Acta 1761, 1515-1522.

Kase, E.T., Thoresen, G.H., Westerlund, S., Hojlund, K., Rustan, A.C., Gaster, M., 2007. Liver X receptor antagonist reduces lipid formation and increases glucose metabolism in myotubes from lean, obese and type 2 diabetic individuals. Diabetologia 50, 2171-2180.

Katz, A., Udata, C., Ott, E., Hickey, L., Burczynski, M.E., Burghart, P., Vesterqvist, O., Meng, X., 2009. Safety, pharmacokinetics, and pharmacodynamics of single doses of LXR-623, a novel liver X-receptor agonist, in healthy participants. J. Clin. Pharm. 49, 643-649.

Kemmerer, M., Wittig, I., Richter, F., Brune, B., Namgaladze, D., 2016. AMPK activates LXRalpha and ABCA1 expression in human macrophages. Int. J. Biochem. Cell Biol. 78, 1-9.

Kennedy, B.K., Berger, S.L., Brunet, A., Campisi, J., Cuervo, A.M., Epel, E.S., Franceschi, C., Lithgow, G.J., Morimoto, R.I., Pessin, J.E., Rando, T.A., Richardson, D., Schadt, E.E., Wyss-Coray, T., Sierra, F., 2014. Geroscience: Linking Aging to Chronic Disease. Cell 159, 709-713.

Khalifa, S.A.M., de Medina, P., Erlandsson, A., El-Seedi, H.R., Silvente-Poirot, S., Poirot, M., 2014. The novel steroidal alkaloids dendrogenin A and B promote proliferation of adult neural stem cells. Biochem. Biophys. Res. Commun. 446, 681-686.

Khosla, S., Farr, J.N., Tchkonia, T., Kirkland, J.L., 2020. The role of cellular senescence in ageing and endocrine disease. Nat. Rev. Endocrinol. 16, 263-275.

Kick, E., Martin, R., Xie, Y., Flatt, B., Schweiger, E., Wang, T.L., Busch, B., Nyman, M., Gu, X.H., Yan, G., Wagner, B., Nanao, M., Nguyen, L., Stout, T., Plonowski, A., Schulman, I., Ostrowski, J., Kirchgessner, T., Wexler, R., Mohan, R., 2015. Liver X receptor (LXR) partial agonists: biaryl pyrazoles and imidazoles displaying a preference for LXRbeta. Bioorg. Med. Chem. Lett. 25, 372-377.

Kick, E.K., Busch, B.B., Martin, R., Stevens, W.C., Bollu, V., Xie, Y., Boren, B.C., Nyman, M.C., Nanao, M.H., Nguyen, L., Plonowski, A., Schulman, I.G., Yan, G., Zhang, H., Hou, X., Valente, M.N., Narayanan, R., Behnia, K., Rodrigues, A.D., Brock, B., Smalley, J., Cantor, G.H., Lupisella, J., Sleph, P., Grimm, D., Ostrowski, J., Wexler, R.R., Kirchgessner, T., Mohan, R., 2016. Discovery of highly potent liver x receptor beta agonists. ACS Med. Chem. Lett. 7, 1207-1212.

Kim, G.H., Oh, G.S., Yoon, J., Lee, G.G., Lee, K.U., Kim, S.W., 2015. Hepatic TRAP80 selectively regulates lipogenic activity of liver X receptor. J. Clin. Invest. 125, 183-193.

Kim, J.H., Jung, D.Y., Kim, H.R., Jung, M.H., 2020. Histone H3K9 Demethylase JMJD2B Plays a Role in LXRalpha-dependent lipogenesis. Int. J. Mol. Sci. 21.
Kim, W.K., Meliton, V., Tetradis, S., Weinmaster, G., Hahn, T.J., Carlson, M., Nelson, S.F., Parham, F., 2010. Osteogenic oxysterol, 20(S)-hydroxycholesterol, induces notch target gene expression in bone marrow stromal cells. J. Bone Min. Res. 25, 782-795.

Kirchessner, T.G., Martin, R., Sleph, P., Grimm, D., Liu, X., Lupisella, J., Smalley, J., Narayanan, R., Xie, Y., Ostrowski, J., Cantor, G.H., Mohan, R., Kick, E., 2015. Pharmacological characterization of a novel liver X receptor agonist with partial LXRalpha activity and a favorable window in nonhuman primates. J. Pharm. Exp. Ther. 352, 305-314.

Kirchessner, T.G., Sleph, P., Ostrowski, J., Lupisella, J., Ryan, C.S., Liu, X., Fernando, G., Grimm, D., Shipkova, P., Zhang, R., Garcia, R., Zhu, J., He, A., Malone, H., Martin, R., Behnia, K., Wang, Z., Barrett, Y.C., Garmise, R.J., Yuan, L., Zhang, J., Gandhi, M.D., Wastall, P., Li, T., Du, S., Salvador, L., Mohan, R., Cantor, G. H., Kick, E., Lee, J., Frost, R.J., 2016. Beneficial and adverse effects of an LXR agonist on human lipid and lipoprotein metabolism and circulating neutrophils. Cell Metab. 24, 223-233.

Kirkland, J.L., Tchkonia, T., 2017. Cellular senescence: a translational perspective. EBioMedicine 21, 21-28.

Kleyer, A., Scholtysek, C., Bottesch, E., Hillienhof, U., Beyer, C., Distler, J.H., Tuckermann, J.P., Schett, G., Kronke, G., 2012. Liver X receptors orchestrate osteoblast/osteoclast crosslink and contact pathologic bone loss. J. Bone Min. Res. 27, 2442-2451.

Komati, R., Spadoni, D., Zheng, S., Sridhar, J., Riley, K.E., Wang, G., 2017. Ligands of therapeutic utility for the liver X receptors. Molecules 22.

Korach-Andre, M., Archer, A., Barros, R.P., Parini, P., Gustafsson, J.A., 2011. Both liver-X receptor (LXR) isoforms control energy expenditure by regulating brown adipose tissue activity. Proc. Natl. Acad. Sci. USA 108, 403-408.

Kratzer, A., Buchemer, M., Pfeifer, T., Becker, T.M., Uray, G., Miyazaki, M., Miyazaki-Anzai, S., Ebner, B., Chandak, P.G., Kadam, R.S., Calayir, E., Rathke, N., Ahammer, H., Radovic, B., Trauner, M., Hoefler, M., Kompella, U.B., Fauler, G., Levi, M., Levak-Frank, S., Kostner, G.M., Kratky, D., 2009. Synthetic LXR agonist attenuates plaque formation in apoE-/- mice without inducing liver steatosis and hypertriglyceridemia. J. Lipid Res. 50, 312-326.

Laffitte, B.A., Chao, L.C., Li, J., Walczak, R., Hummasti, S., Joseph, S.B., Castrillo, A., Wilpitz, D.C., Mangelsdorf, D.J., Collins, J.L., Saez, E., Tontonoz, P., 2003. Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue. Proc. Natl. Acad. Sci. USA 100, 5419-5424.

Lehmann, J.M., Kliewer, S.A., Moore, L.B., Smith-Oliver, T.A., Oliver, B.B., Su, J.L., Sundseth, S.S., Winegar, D.A., Blanchard, D.E., Spencer, T.A., Willson, T.M., 1997. Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J. Biol. Chem. 272, 3137-3140.

Leidal, A.M., Levine, B., Debnath, J., 2018. Autophagy and the cell biology of age-related disease. Nat. Cell Biol. 20, 1338-1348.

Li, X., Zhang, S., Blander, G., Tse, J.G., Krieger, M., Guarente, L., 2007. SIRT1 deacetylates and positively regulates the nuclear receptor LXR. Mol. Cell 28, 91-106.

Limbad, C., Doi, R., McGirr, J., Ciotlos, S., Perez, K., Clayton, Z.S., Daya, R., Seals, D.R., Campisi, J., Melov, S., 2022. Senolysis induced by 25-hydroxycholesterol targets CRYAB in multiple cell types. iScience 25, 103848.

Lin, C.Y., Gustafsson, J.A., 2015. Targeting liver X receptors in cancer therapeutics. Nat. Rev. Cancer 15, 216-224.

Lin, J., Wang, F., Jiang, G., Zhang, T., Zhang, J., He, Q., Fan, Y., 2022. LXR activation ameliorates high glucose stress-induced aberrant mitochondrial dynamics via downregulation of Calpain1 expression in H9c2 cardiomyoblasts. Biochem. Biophys. Res. Commun. 614, 145-152.

Liu, Y., Wei, Z., Zhang, Y., Ma, X., Chen, Y., Yu, M., Ma, C., Li, X., Cao, Y., Liu, J., Han, J., Yang, X., Duan, Y., 2018. Activation of liver X receptor plays a central role in啟动actions of 25-hydroxycholesterol. J. Lipid Res. 59, 2287-2296.

Lo Sasso, G., Bovenga, F., Murzilli, S., Salvatore, L., Di Tullio, G., Martelli, N., D'Orazio, A., Rainaldi, S., Vacca, M., Mangia, D., Palascandra, G., Moschetta, A., 2013. Liver X receptors inhibit proliferation of human colorectal cancer cells and growth of intestinal tumors in mice. Gastroenterology 144, 1497-1507.

Lopez-Otin, C., Pietrocola, F., Roiz-Valle, D., Galluzzi, L., Kroemer, G., 2023b. Meta-hallmarks of aging and cancer. Cell Metab. 35, 12-35.

Lopez-Otin, C., Blasco, M.A., Partridge, L., Serrano, M., Kroemer, G., 2023a. Hallmarks of aging: an expanding universe. Cell 186, 243-278.

López-Otin, C., Blasco, M.A., Partridge, L., Serrano, M., Kroemer, G., 2013. The hallmarks of aging. Cell 153, 1194-1217.

Ma, L., Vidana Gamage, H.E., Tiwari, S., Han, C., Henn, M.A., Krawczynska, N., Dibaeinia, P., Koelwyn, G.J., Das Gupta, A., Bautista Rivas, R.O., Wright, C.L., Xu, F., Moore, K.J., Sinha, S., Nelson, E.R., 2022. The liver X receptor is selectively modulated to differentially alter female mammary metastasis-associated myeloid cells. Endocrinology 163.

Mackenbach, J.P., Kunst, A.E., Lautenbach, H., Oei, Y.B., Bijlsma, F., 1999. Gains in life expectancy after elimination of major causes of death: revised estimates taking into account the effect of competing causes. J. Epidemiol. Community Health 53, 32-37.

Manini, T.M., 2010. Energy expenditure and aging. Ageing Res Rev. 9, 1-11.

Marathe, C., Bradley, M.N., Hong, C., Lopez, F., Ruiz de Galarreta, C.M., Tontonoz, P., Castrillo, A., 2006. The arginase II gene is an anti-inflammatory target of liver X receptor, in macrophages. J. Biol. Chem. 281, 32197-32206.

Marengo, B., Bellora, F., Ricciarelli, R., De Ciucis, C., Furfaro, A., Leardi, R., Colla, R., Pacini, D., Traverso, M., Moretta, A., Pronzato, M.A., Bottino, C., Domenicotti, C., 2016. Oxysterol mixture and, in particular, 27-hydroxycholesterol drive M2 polarization of human macrophages. Bio factors 42, 80-92.

Martinez, D., Pentinat, T., Ribo, S., Daviaud, C., Bloks, W.V., Cebria, J., Villalmanzo, N., Kalko, S.G., Ramon-Krauel, M., Diaz, R., Plosch, T., Tost, J., Jimenez-Chillaron, J.C., 2014. In utero undernutrition in male mice programs liver lipid metabolism in the

second-generation offspring involving altered Lxrα DNA methylation. Cell Metab. 19, 941-951.

Martinez-Martinez, A.B., Torres-Perez, E., Devanney, N., Del Moral, R., Johnson, L.A., Arbones-Mainar, J.M., 2020. Beyond the CNS: The many peripheral roles of APOE. Neurobiol. Dis. 138, 104809.

Matsushita, K., Morello, F., Zhang, Z., Masuda, T., Iwanaga, S., Steffensen, K.R., Gustafsson, J.A., Pratt, R.E., Dzau, V.J., 2016. Nuclear hormone receptor LXRalpha inhibits adipocyte differentiation of mesenchymal stem cells with Wnt/beta-catenin signaling. Lab. Invest. 96, 230-238.

Mayi, T.H., Rigamonti, E., Pattou, F., Staels, B., Chinetti-Gbaguidi, G., 2011. Liver X Receptor (LXR) activation negatively regulates visfatin expression in macrophages. Biochem. Biophys. Res. Commun. 404, 458-462.

McGaun, J., Baur, J.A., 2023. Taurine linked with healthy aging. Science 380, 1010-1011.

McKenna, N.J., Lanz, R.B., O'Malley, B.W., 1999. Nuclear receptor coregulators: cellular and molecular biology. Endocr. Rev. 20, 321-344.

de Medina, P., Paillasse, M.R., Payré, B., Silvente-Poirot, S., Poirot, M., 2009. Synthesis of new alkylaminooxysterols with potent cell differentiating activities: identification of leads for the treatment of cancer and neurodegenerative diseases. J. Med. Chem. 52, 7765-7777.

de Medina, P., Paillasse, M.R., Segala, G., Voisin, M., Mhamdi, L., Dalenc, F., Lacroix- Triki, M., Filleron, T., Pont, F., Saati, T.A., Morisseau, C., Hammock, B.D., Silvente- Poirot, S., Poirot, M., 2013. Dendrogenin A arises from cholesterol and histamine metabolism and shows cell differentiation and anti-tumour properties. Nat. Commun. 4, 1840.

de Medina, P., Silvente-Poirot, S., Poirot, M., 2022. Oxysterols are potential physiological regulators of aging. Ageing Res. Rev. 77, 101615.

de Medina, P., Ayadi, S., Soules, R., Payre, B., Rup-Jacques, S., Silvente-Poirot, S., Samadi, M., Poirot, M., 2023a. Chemical synthesis and biochemical properties of cholestane-5alpha,6beta-diol-3-sulfonate: a non-hydrolysable analogue of cholestane-5alpha,6beta-diol-3beta-sulfate. J. Steroid Biochem. Mol. Biol. 234, 106396.

de Medina, P., Bunay, J., Poirot, M., Record, M., Silvente-Poirot, S., 2023b. Targeting NR1H1/liver X receptor with dendrogenin A differentiates tumor cells to activate a new secretory pathway releasing immunogenic anti-tumor vesicles enriched in LC3-II-associated exosomes. Autophagy 19, 1036-1038.

Meng, Z.X., Yin, Y., Lv, J.H., Sha, M., Lin, Y., Gao, L., Zhu, Y.X., Sun, Y.J., Han, X., 2012. Aberrant activation of liver X receptors impairs pancreatic beta cell function through upregulation of sterol regulatory element-binding protein 1c in mouse islets and rodent cell lines. Diabetologia 55, 1733-1744.

Milosic, F., Hengstschlager, M., Osmanagic-Myers, S., 2023. Premature aging in genetic diseases: what conclusions can be drawn for physiological aging. Front. Cell 4, 1327833.

Mita, M.M., Mita, A.C., Chmielowski, B., Hamilton, E.P., Pant, S., Waldman, R.J., Rowinsky, E.K., Szarek, M., Gonsalves, F., Kurth, I., Andreu, C., Busby, R., Darst, D. M., Tavazoie, S.S., Tavazoie, M., Postow, M.A., 2018. Pharmacodynamic and clinical activity of RGX-104, a first-in-class immunotherapy targeting the liver-X nuclear hormone receptor (LXR), in patients with refractory malignancies. Journal of Clinical Oncology 36, 3095. https://doi.org/10.1200/jco.2018.36.15_suppl.3095.

Mizushima, N., Levine, B., Cuervo, A.M., Klionsky, D.J., 2008. Autophagy fights disease through cellular self-digestion. Nature 451, 1069-1075.

Moojaart, S.P., Kuningas, M., Westendorp, R.G.J., Houwing-Duistermaat, J.J., Slagboom, P.E., Rensen, P.C.N., van Heemst, D., 2007. Liver X receptor alpha associates with human life span. J. Gerontol. Ser. A. Biol. Sci. Med. Sci. 62, 343-349.

Mouchel, P.L., Serhan, N., Betous, R., Farge, T., Saland, E., De Medina, P., Hoffmann, J. S., Sarry, J.E., Poirot, M., Silvente-Poirot, S., Recher, C., 2020. Dendrogenin A enhances anti-leukemic effect of anthracycline in acute myeloid leukemia. Cancer 12.

Muse, E.D., Yu, S., Edillor, C.R., Tao, J., Spann, N.J., Troutman, T.D., Seidman, J.S., Henke, A., Roland, J.T., Ozeki, K.A., Thompson, B.M., McDonald, J.G., Bahadorani, J., Tsimikas, S., Grossman, T.R., Tremblay, M.S., Glass, C.K., 2018. Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macrophages. Proc. Natl. Acad. Sci. USA 115, E4680-E4689.

N, A.G., Bensinger, S.J., Hong, C., Beceiro, S., Bradley, M.N., Zelcer, N., Deniz, J., Ramirez, C., Diaz, M., Gallardo, G., de Galarreta, C.R., Salazar, J., Lopez, F., Edwards, P., Parks, J., Andujar, M., Tontonoz, P., Castrillo, A., 2009. Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity 31, 245-258.

Navarro, C.L., Cau, P., Levy, N., 2006. Molecular bases of progeroid syndromes. Hum. Mol. Genet. 15 (2), R151-R161.

Nelson, E.R., DuSell, C.D., Wang, X., Howe, M.K., Evans, G., Michalek, R.D., Umetani, M., Rathmell, J.C., Khosla, S., Gesty-Palmer, D., McDonnell, D.P., 2011. The oxysterol, 27-hydroxycholesterol, links cholesterol metabolism to bone homeostasis through its actions on the estrogen and liver X receptors. Endocrinology 152, 4691-4705.

Nelson, E.R., Wardell, S.E., Jasper, J.S., Park, S., Suchindran, S., Howe, M.K., Carver, N. J., Pillai, R.V., Sullivan, P.M., Sondhi, V., Umetani, M., Geradts, J., McDonnell, D.P., 2013. 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Science 342, 1094-1098.

Nguyen, T.T.T., Ishida, C.T., Shang, E., Shu, C., Torrini, C., Zhang, Y., Bianchetti, E., Sanchez-Quintero, M.J., Kleiner, G., Quinzii, C.M., Westhoff, M.A., Karpel-Massler, G., Canoll, P., Siegelin, M.D., 2019. Activation of LXRbeta inhibits tumor respiration and is synthetically lethal with Bcl-xL inhibition. EMBO Mol. Med. 11, e10769.
Nilsson, M., Stulnig, T.M., Lin, C.Y., Yeo, A.L., Nowotny, P., Liu, E.T., Steffensen, K.R., 2007. Liver X receptors regulate adrenal steroidogenesis and hypothalamic-pituitary-adrenal feedback. Mol. Endocrinol. 21, 126-137.

Nomura, S., Endo-Umeda, K., Aoyama, A., Makishima, M., Hashimoto, Y., Ishikawa, M., 2015. Styrylphenylphthalimides as novel transrepression-selective liver X receptor (LXR) modulators. ACS Chem. Lett. 6, 902-907.

Ohno, R., Mainka, R., Kirchhoff, R., Hartung, N.M., Schebb, N.H., 2024. Sterol derivatives specifically increase anti-inflammatory oxylin formation in M2-like macrophages by LXR-mediated induction of 15-LOX. Molecules 29.

Ou, Z., Jiang, M., Hu, B., Huang, Y., Xu, M., Ren, S., Li, S., Liu, S., Xie, W., Huang, M., 2014. Transcriptional regulation of human hydroxysteroid sulfotransferase SULT2A1 by LXRalpha. Drug Metab. Dispos. 42, 1684-1689.

Paillasse, M.R., de Medina, P., 2015. The NR4A nuclear receptors as potential targets for anti-aging interventions. Med. Hypotheses 84, 135-140.

Pehkonen, P., Welter-Stahl, L., Diwo, J., Ryynanen, J., Wienecke-Baldacchino, A., Heikkinen, S., Treuter, E., Steffensen, K.R., Carlberg, C., 2012. Genome-wide landscape of liver X receptor chromatin binding and gene regulation in human macrophages. BMC Genom. 13, 50.

Pencheva, N., Buss, C.G., Posada, J., Merghoub, T., Tavazoie, S.F., 2014. Broad-spectrum therapeutic suppression of metastatic melanoma through nuclear hormone receptor activation. Cell 156, 986-1001.

Penvose, A., Keenan, J.L., Bray, D., Ramlall, V., Siggers, T., 2019. Comprehensive study of nuclear receptor DNA binding provides a revised framework for understanding receptor specificity. Nat. Commun. 10, 2514.

Poirot, M., Silvente-Poirot, S., 2013. Cholesterol-5,6-epoxides: chemistry, biochemistry, metabolic fate and cancer. Biochimie 95, 622-631.

Poirot, M., Silvente-Poirot, S., 2018. The tumor-suppressor cholesterol metabolite, dendrogenin A, is a new class of LXR modulator activating lethal autophagy in cancers. Biochem. Pharmacol. 153, 75-81.

Pommier, A.J., Dufour, J., Alves, G., Viennois, E., De Boussac, H., Trousson, A., Volle, D. H., Caira, F., Val, P., Arnaud, P., Lobaccaro, J.M., Baron, S., 2013. Liver X receptors protect from development of prostatic intra-epithelial neoplasia in mice. PLoS Gen. 9, e1003483.

Quinet, E.M., Basso, M.D., Halpern, A.R., Yates, D.W., Steffan, R.J., Clerin, V., Resmini, C., Keith, J.C., Berrodin, T.J., Feingold, I., Zhong, W., Hartman, H.B., Evans, M.J., Gardell, S.J., DiBlasio-Smith, E., Mounts, W.M., LaVallie, E.R., Wrobel, J., Nambi, P., Vlasuk, G.P., 2009. LXR ligand lowers LDL cholesterol in primates, is lipid neutral in hamster, and reduces atherosclerosis in mouse. J. Lipid Res. 50, 2358-2370.

Raccosta, L., Marinozzi, M., Costantini, S., Maggioni, D., Ferreira, L.M., Corna, G., Zordan, P., Sorice, A., Farinello, D., Bianchessi, S., Riba, M., Lazarevic, D., Provero, P., Mack, M., Bondanza, A., Navarte, I., Gustafsson, J.A., Ranzani, V., De Sanctis, F., Ugel, S., Baron, S., Lobaccaro, J.A., Pontini, L., Pacciarini, M., Traversari, C., Pagani, M., Bronte, V., Sitia, G., Antonson, P., Brendolan, A., Budillon, A., Russo, V., 2023. Harnessing the derived cholesterol transport pathway to favor differentiation of monocyte-derived APCs and antitumor responses. Cell Death Dis. 14, 129.

Ramon-Vazquez, A., de la Rosa, J.V., Tabraue, C., Castrillo, A., 2019. Bone marrow-derived macrophage immortalization of LXR nuclear receptor-deficient cells. Methods Mol. Biol. 1951, 75-85.

Record, M., Attia, M., Carayon, P., Pucheu, L., Bunay, J., Soules, R., Ayadi, S., Payre, B., Perrin-Cocon, L., Bourgailh, F., Lamaziere, A., Lotteau, V., Poirot, M., Silvente-Poirot, S., de Medina, P., 2022. Targeting the liver X receptor with dendrogenin A differentiates tumour cells to secrete immunogenic exosome-enriched vesicles. J. Extra Vesicles 11, e12211.

ReFaey, K., Tripathi, S., Grewal, S.S., Bhargav, A.G., Quinones, D.J., Chaichana, K.L., Antwi, S.O., Cooper, L.T., Meyer, F.B., Dronca, R.S., Diasio, R.B., Quinones-Hinojosa, A., 2021. Cancer mortality rates increasing vs cardiovascular disease mortality decreasing in the world: future implications. Mayo Clin. Proc. Innov. Qual. Outcomes 5, 645-653.

Remen, K.M., Henning, P., Lerner, U.H., Gustafsson, J.A., Andersson, G., 2011. Activation of liver X receptor (LXR) inhibits receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclast differentiation in an LXRbeta-dependent mechanism. J. Biol. Chem. 286, 33048-33094.

Ren, J., Zhang, Y., 2018. Targeting autophagy in aging and aging-related cardiovascular diseases. Trends Pharmac. Sci. 39, 1064-1076.

Repa, J.J., Liang, G., Ou, J., Bashmakov, Y., Lobaccaro, J.M., Shimomura, I., Shan, B., Brown, M.S., Goldstein, J.L., Mangelsdorf, D.J., 2000. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev. 14, 2819-2830.

Ridker, P.M., Everett, M., Thuren, T., MacFadyen, J.G., Chang, W.H., Ballantyne, C., Fonseca, F., Nicolau, J., Koenig, W., Anker, S.D., Kastelein, J.J.P., Cornel, J.H., Pais, P., Pella, D., Genest, J., Cifkova, R., Lorenzatti, A., Forster, L., Kobalava, Z., Vida-Simiti, L., Flather, M., Shimokawa, H., Ogawa, H., Dellborg, M., Rossi, P.R.F., Troquay, R.P.T., Libby, P., Glynn, R.J., Group, C.T., 2017. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119-1131.

Robbins, P.D., Jurk, D., Khosla, S., Kirkland, J.L., LeBrasseur, N.K., Miller, J.D., Passos, J. F., Pignolo, R.J., Tchonia, T., Niedernhofer, L.J., 2021. Senolytic drugs: reducing senescent cell viability to extend health span. Annu. Rev. Pharmacol. Toxicol. 61, 779-803.

Rodrigo, S., Fauste, E., de la Cuesta, M., Ruizaga, L., Alvarez-Millan, J.J., Panadero, M. I., Otero, P., Bocos, C., 2018. Maternal fructose induces gender-dependent changes in both LXRalpha promoter methylation and cholesterol metabolism in progeny. J. Nutr. Biochem. 61, 163-172.

Rolland, Y., Sierra, F., Ferrucci, L., Barzilai, N., De Cabo, R., Mannick, J., Oliva, A., Evans, W., Angioni, D., De Souto Barreto, P., Raffin, J., Vellas, B., Kirkland, J.L.,

group, G.C.T.T. 2023. Challenges in developing Geroscience trials. Nat. Commun. 14, 5038.

Rong, X., Albert, C.J., Hong, C., Duerr, M.A., Chamberlain, B.T., Tarling, E.J., Ito, A., Gao, J., Wang, B., Edwards, P.A., Jung, M.E., Ford, D.A., Tontonoz, P., 2013. LXRs regulate ER stress and inflammation through dynamic modulation of membrane phospholipid composition. Cell Metab. 18, 685-697.

Sacchetti, P., Sousa, K.M., Hall, A.C., Liste, I., Steffensen, K.R., Theofilopoulos, S., Parish, C.L., Hazenberg, C., Richter, L.A., Hovatta, O., Gustafsson, J.A., Arenas, E., 2009. Liver X receptors and oxysterols promote ventral midbrain neurogenesis in vivo and in human embryonic stem cells. Cell Stem Cell 5, 409-419.

Saliba-Gustafsson, P., Pedrelli, M., Gertow, K., Werngren, O., Janas, V., Pourteymour, S., Baldassarre, D., Tremoli, E., Veglia, F., Rauramaa, R., Smit, A.J., Giral, P., Kurl, S., Pirro, M., de Faire, U., Humphries, S.E., Hamsten, A., Group, I.S., Goncalves, I., Orho-Melander, M., Franco-Cereceda, A., Boren, J., Eriksson, P., Magne, J., Parini, P., Ehrenborg, E., 2019. Subclinical atherosclerosis and its progression are modulated by PLIN2 through a feed-forward loop between LXR and autophagy. J. Intern. Med. 286, 660-675.

Sandoval-Hernandez, A.G., Hernandez, H.G., Restrepo, A., Munoz, J.I., Bayon, G.F., Fernandez, A.F., Fraga, M.F., Cardona-Gomez, G.P., Arboleda, H., Arboleda, G.H., 2016a. Liver X receptor agonist modifies the DNA methylation profile of synapse and neurogenesis-related genes in the triple transgenic mouse model of Alzheimer's disease. J. Mol. Neurosci. 58, 243-253.

Sandoval-Hernandez, A.G., Restrepo, A., Cardona-Gomez, G.P., Arboleda, G., 2016b. LXR activation protects hippocampal microvasculature in very old triple transgenic mouse model of Alzheimer's disease. Neurosci. Lett. 621, 15-21.

Schmidt, A.F., Hunt, N.B., Gordillo-Maranón, M., Charoen, P., Drenos, F., Kivimaki, M., Lawlor, D.A., Giambartolomei, C., Papacosta, O., Chaturvedi, N., Bis, J.C., O'Donnell, C.J., Wannamethee, G., Wong, A., Price, J.F., Hughes, A.D., Gaunt, T.R., Franceschini, N., Mook-Kanamori, D.O., Zwierzyna, M., Sofat, R., Hingorani, A.D., Finan, C., 2021. Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease. Nat. Commun. 12, 5640.

Schmutz, M., Jiang, Y.J., Dubrac, S., Elias, P.M., Feingold, K.R., 2008. Thematic review series: skin lipids. Peroxisome proliferator-activated receptors and liver X receptors in epidermal biology. J. Lipid Res. 49, 499-509.

Schroeppfer, G.J., 2000. Oxysterols: modulators of cholesterol metabolism and other processes. Physiol. Rev. 80, 361-554.

Schulman, I.G., 2017. Liver X receptors link lipid metabolism and inflammation. FEBS Lett. 591, 2978-2991.

Schultz, J.R., Tu, H., Luk, A., Repa, J.J., Medina, J.C., Li, L., Schwendner, S., Wang, S., Toolen, M., Mangelsdorf, D.J., Lustig, K.D., Shan, B., 2000. Role of LXRs in control of lipogenesis. Genes Dev. 14, 2831-2838.

Schultz, M.B., Sinclair, D.A., 2016. When stem cells grow old: phenotypes and mechanisms of stem cell aging. Development 143, 3-14.

Sciorati, C., Gamberale, R., Monno, A., Citterio, L., Lanzani, C., De Lorenzo, R., Ramirez, G.A., Esposito, A., Manunta, P., Manfredi, A.A., Rovere-Querini, P., 2020. Pharmacological blockade of TNFalpha prevents sarcopenia and prolongs survival in aging mice. Aging 12, 23497-23508.

Segala, G., de Medina, P., Iuliano, L., Zerbinati, C., Paillasse, M.R., Noguer, E., Dalenc, F., Payré, B., Jordan, V.C., Record, M., Silvente-Poirot, S., Poirot, M., 2013. 5,6-Epoxy-cholesterols contribute to the anticancer pharmacology of Tamoxifen in breast cancer cells. Biochem. Pharmacol. 86, 175-189.

Segala, G., David, M., de Medina, P., Poirot, M.C., Serhan, N., Vergez, F., Mougel, A., Saland, E., Carayon, K., Leignadier, J., Caron, N., Voisin, M., Cherier, J., Ligat, L., Lopez, F., Noguer, E., Rives, A., Payré, B., Saati, T., Chaturziere, A., Despres, G., Lobaccaro, J.-M., Baron, S., Demur, C., de Toni, F., Larrue, C., Boutzen, H., Thomas, F., Sarry, J.-E., Tosolini, M., Picard, D., Record, M., Récher, C., Poirot, M., Silvente-Poirot, S., 2017. Dendrogenin A drives LXR to trigger lethal autophagy in cancers. Nat. Commun. 8, 1903.

Serhan, N., Mouchel, P.L., Medina, P., Segala, G., Mougel, A., Saland, E., Rives, A., Lamaziere, A., Despres, G., Sarry, J.E., Larrue, C., Vergez, F., Largeaud, L., Record, M., Recher, C., Silvente-Poirot, S., Poirot, M., 2020. Dendrogenin A synergizes with Cytarabine to Kill Acute Myeloid Leukemia Cells In Vitro and In Vivo. Cancers 12.

Shin, W., Alpaugh, W., Hallihan, L.J., Sinha, S., Crowther, E., Martin, G.R., Scheidl-Yee, T., Yang, X., Yoon, G., Goldsmith, T., Berger, N.D., de Almeida, L.G., Dufour, A., Dobrinski, I., Weinfeld, M., Jirik, F.R., Biernaskie, J., 2021. PNKP is required for maintaining the integrity of progenitor cell populations in adult mice. Life Sci. Alliance 4.

Shinohara, M., Kanekiyo, T., Tachibana, M., Kurti, A., Shinohara, M., Fu, Y., Zhao, J., Han, X., Sullivan, P.M., Rebeck, G.W., Fryer, J.D., Heckman, M.G., Bu, G., 2020. APOE2 is associated with longevity independent of Alzheimer's disease. eLife 9, e62199.

Silvente-Poirot, S., Segala, G., Poirot, M.C., Poirot, M., 2018b. Ligand-dependent transcriptional induction of lethal autophagy: A new perspective for cancer treatment. Autophagy 14, 555-557.

Silvente-Poirot, S., Dalenc, F., Poirot, M., 2018a. The effects of cholesterol-derived oncometabolites on nuclear receptor function in cancer. Cancer Res. 78, 4803-4808.

Sim, W.C., Park, S., Lee, K.Y., Je, Y.T., Yin, H.Q., Choi, Y.J., Sung, S.H., Park, S.J., Park, H.J., Shin, K.J., Lee, B.H., 2014. LXR-alpha antagonist meso-dihydroguaiaretic acid attenuates high-fat diet-induced nonalcoholic fatty liver. Biochem. Pharm. 90, 414-424.

Sim, W.C., Kim, D.G., Lee, K.J., Choi, Y.J., Choi, Y.J., Shin, K.J., Jun, D.W., Park, S.J., Park, H.J., Kim, J., Oh, W.K., Lee, B.H., 2015. Cinnamamides, novel liver X receptor antagonists that inhibit ligand-induced lipogenesis and fatty liver. J. Pharm. Exp. Ther. 355, 362-369.
Singh, M., Jain, M., Bose, S., Halder, A., Nag, T.C., Dinda, A.K., Mohanty, S., 2021. 22(R)-
hydroxycholesterol for dopaminergic neuronal specification of MSCs
and amelioration of Parkinsonian symptoms in rats. Cell Death Discov 7, 13.

Singh, P., Gollapalli, K., Mangiola, S., Schranner, D., Yusuf, M.A., Chamoli, M., Shi, S.L., Lopes Bastos, B., Nair, T., Riermeier, A., Vayndor, E.M., Wu, J.Z., Nilakhe, A., Nguyen, C.Q., Muir, M., Kiflezghi, M.G., Foulger, A., Junker, A., Devine, J., Shanar, K., Chinta, S.J., Rajput, S., Rane, A., Baumert, P., Schonfelder, M., Iavarone, F., di Lorenzo, G., Kumari, S., Gupta, A., Sarkar, R., Khyriem, C., Chawla, A.S., Sharma, A., Sarper, N., Chattopadhyay, N., Biswal, B.K., Settembre, C., Nagarajan, P., Targoff, K.L., Picard, M., Gupta, S., Velagapudi, V., Papenfuss, A.T., Kaya, A., Ferreira, M.G., Kennedy, B.K., Andersen, J.K., Lithgow, G.J., Ali, A.M., Mukhopadhyay, A., Palotie, A., Kastenmuller, G., Kaeberlein, M., Wackerhage, H., Pal, B., Yadav, V.K., 2023. Taurine deficiency as a driver of aging. Science 380, eabn9257.

Song, X., Wu, W., Warner, M., Gustafsson, J.A., 2022a. Liver X receptor regulation of glial cell functions in the CNS. Biomedicines 10.

Song, X.Y., Wu, W.F., Dai, Y.B., Xu, H.W., Roman, A., Wang, L., Warner, M., Gustafsson, J.A., 2022b. Ablation of Liver X receptor beta in mice leads to overactive macrophages and death of spiral ganglion neurons. Hear Res 422, 108534.

Srivastava, S., 2016. Emerging therapeutic roles for NAD(+) metabolism in mitochondrial and age-related disorders. Clin. Transl. Med. 5, 25.

Steffensen, K.R., Gustafsson, J.A., 2004. Putative metabolic effects of the liver X receptor (LXR). Diabetes 53 (1), S36-S42.

van Straten, E.M., Bloks, V.W., Huijkmans, N.C., Baller, J.F., van Meer, H., Lutjohann, D., Kuipers, F., Plosch, T., 2010. The liver X-receptor gene promoter is hypermethylated in a mouse model of prenatal protein restriction. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298, R275-282.

Sun, T., Li, Y.J., Tian, Q.Q., Wu, Q., Feng, D., Xue, Z., Guo, Y.Y., Yang, L., Zhang, K., Zhao, M.G., Wu, Y.M., 2018. Activation of liver X receptor beta-enhancing neurogenesis ameliorates cognitive impairment induced by chronic cerebral hypoperfusion. Exp. Neurol. 304, 21-29.

Tamura, S., Okada, M., Kato, S., Shinoda, Y., Shioda, N., Fukunaga, K., Ui-Tei, K., Ueda, M., 2018. Ouabagenin is a naturally occurring LXR ligand without causing hepatic steatosis as a side effect. Sci. Rep. 8, 2305.

Tavazoe, M.F., Pollack, I., Tanqueco, R., Ostendorf, B.N., Reis, B.S., Gonsalves, F.C., Kurth, I., Andreu-Agullo, C., Derbyshire, M.L., Posada, J., Takeda, S., Tafreshian, K. N., Rowinsky, E., Szarek, M., Waltzman, R.J., McMillan, E.A., Zhao, C., Mita, M., Mita, A., Chmielowski, B., Postow, M.A., Ribas, A., Mucida, D., Tavazoe, S.F., 2018. LXR/ApoE activation restricts innate immune suppression in cancer. Cell 172, 825-840 e818.

Terao, R., Lee, T.J., Colasanti, J., Pfeifer, C.W., Lin, J.B., Santeford, A., Hase, K., Yamaguchi, S., Du, D., Sohn, B.S., Sasaki, Y., Yoshida, M., Apte, R.S., 2024. LXR/CD38 activation drives cholesterol-induced macrophage senescence and neurodegeneration via NAD(+)-depletion. Cell Rep 43, 114102.

Thomas, D.G., Doran, A.C., Fotakis, P., Westerterp, M., Antonson, P., Jiang, H., Jiang, X. C., Gustafsson, J.A., Tabas, I., Tall, A.R., 2018. LXR suppresses inflammatory gene expression and neutrophil migration through cis-sulfation and cholesterol efflux. Cell Rep. 25, 3774-3785 e3774.

Thondamal, M., Witting, M., Schmitt-Kopplin, P., Aguilaniu, H., 2014. Steroid hormone signalling links reproduction to lifespan in dietary-restricted Caenorhabditis elegans. Nat. Commun. 5, 4879.

Torocisk, D., Barath, M., Benko, S., Szeles, L., Dezso, B., Poliska, S., Hegyi, Z., Homolya, L., Szatmari, I., Lanyi, A., Nagy, L., 2010. Activation of liver X receptor sensitizes human dendritic cells to inflammatory stimuli. J. Immunol. 184, 5456-5465.

Trifunovic, A., Wredenberg, A., Falkenberg, M., spelbrink, J.N., Rovio, A.T., Bruder, C.E., Trifoloy, Y.M., Gidlof, S., Oldfors, A., Wibom, R., Tornell, J., Jacobs, H.T., Larsson, N.G., 2004. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417-423.

Trumble, B.C., Charifson, M., Kraft, T., Garcia, A.R., Cummings, D.K., Hooper, P., Lea, A. J., Eid Rodriguez, K., Koebele, S.V., Buetow, K., Beheim, B., Minocher, R., Gutierrez, M., Thomas, G.S., Gatz, M., Stieglitz, J., Finch, C.E., Kaplan, H., Gurven, M., 2023. Apolipoprotein-epsilon4 is associated with higher fecundity in a natural fertility population. Sci. Adv. 9, eade9797.

Uebanso, T., Taketani, Y., Yamamoto, H., Amo, K., Tanaka, S., Arai, H., Takei, Y., Masuda, M., Yamanaka-Okumura, H., Takeda, E., 2012. Liver X receptor negatively regulates fibroblast growth factor 21 in the fatty liver induced by cholesterol-enriched diet. J. Nutr. Biochem. 23, 785-790.

Vedin, L.L., Gustafsson, J.A., Steffensen, K.R., 2013. The oxysterol receptors LXRalpha and LXRbeta suppress proliferation in the colon. Mol. Carcinol. 52, 835-844.

Viennois, E., Mouzat, K., Dufour, J., Morel, L., Lobaccaro, J.M., Baron, S., 2012. Selective liver X receptor modulators (SLiMs): what use in human health? Mol. Cell Endocrinol. 351, 129-141.

Villablanca, E.J., Raccosta, L., Zhou, D., Fontana, R., Maggioni, D., Negro, A., Sanvito, F., Ponzoni, M., Valentinis, B., Bregni, M., Prinetti, A., Steffensen, K.R., Sonnino, S., Gustafsson, J.A., Doglioni, C., Bordignon, C., Traversari, C., Russo, V., 2010. Tumor-mediated liver X receptor-alpha activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses. Nat. Med. 16, 98-105.

Volle, D.H., Mouzat, K., Duggavathi, R., Siddeek, B., Dechelotte, P., Sion, B., Veysiere, G., Benahmed, M., Lobaccaro, J.M., 2007. Multiple roles of the nuclear receptors for oxysterols liver X receptor to maintain male fertility. Mol. Endocrinol. 21, 1014-1027.

Wagner, B.L., Valledor, A.F., Shao, G., Daige, C.L., Bischoff, E.D., Petrowski, M., Jepsen, K., Baek, S.H., Heyman, R.A., Rosenfeld, M.G., Schulman, I.G., Glass, C.K.,

2003. Promoter-specific roles for liver X receptor/corepressor complexes in the regulation of ABCA1 and SREBP1 gene expression. Mol. Cell Biol. 23, 5780-5789.

Wang, B., Tontonoz, P., 2018. Liver X receptor in lipid signalling and membrane homeostasis. Nat. Rev. Endocrinol. 14, 452-463.

Wang, N.Q., Sun, P.X., Shen, Q.Q., Deng, M.Y., 2025. Cholesterol metabolism in CNS diseases: the potential of SREBP2 and LXR as therapeutic targets. Mol. Neurobiol. 62, 6283-6307.

Wang, Y., Chen, L., Pandak, W.M., Heuman, D., Hylemon, P.B., Ren, S., 2020a. High glucose induces lipid accumulation via 25-hydroxycholesterol DNA-CpG methylation. iScience 23, 101102.

Wang, Y., Li, X., Ren, S., 2020b. Cholesterol metabolites 25-hydroxycholesterol and 25-hydroxycholesterol 3-sulfate are potent paired regulators: from discovery to clinical usage. Metabolites 11.

Wang, Y., Lin, W., Brown, J.E., Chen, L., Pandak, W.M., Hylemon, P.B., Ren, S., 2021. 25-Hydroxycholesterol 3-sulfate is an endogenous ligand of DNA methyltransferases in hepatocytes. J. Lipid Res. 62, 100063.

Wang, Y., Ren, J., Ren, S., 2024. LARSucosterol: endogenous epigenetic regulator for treating chronic and acute liver diseases. Am. J. Physiol. Endocrinol. Metab. 326, E577-E587.

Weikum, E.R., Liu, X., Ortlund, E.A., 2018. The nuclear receptor superfamily: a structural perspective. Protein Sci. 27, 1876-1892.

Whitton, H., Singh, L.N., Patrick, M.A., Price, A.J., Osorio, F.G., Lopez-Otin, C., Bochkis, I.M., 2018. Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver. Aging Cell 17, e12742.

Williams, G.C., 2001. Pleiotropy, natural selection, and the evolution of senescence. Sci. Aging Knowl. Environ. 2001, cp13.

Williams, S., Bledsoe, R.K., Collins, J.L., Boggs, S., Lambert, M.H., Miller, A.B., Moore, J., McKee, D.D., Moore, L., Nichols, J., Parks, D., Watson, M., Wisely, B., Willson, T.M., 2003. X-ray crystal structure of the liver X receptor beta ligand binding domain: regulation by a histidine-tryptophan switch. J. Biol. Chem. 278, 27138-27143.

Willy, P.J., Umesono, K., Ong, E.S., Evans, R.M., Heyman, R.A., Mangelsdorf, D.J., 1995. LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev. 9, 1033-1045.

Wu, N., Zheng, W., Zhou, Y., Tian, Y., Tang, M., Feng, X., Ashrafizadeh, M., Wang, D., Niu, X., Tambuwala, M., Wang, L., Tergaonkar, V., Sethi, G., Klionsky, D., Huang, L., Gu, M., 2024. Autophagy in aging-related diseases and cancer: Principles, regulatory mechanisms and therapeutic potential. Ageing Res. Rev. 100, 102428.

Xu, L., Kim, J.K., Bai, Q., Zhang, X., Kakiyama, G., Min, H.K., Sanyal, A.J., Pandak, W.M., Ren, S., 2013. 5-cholesten-3beta,25-diol 3-sulfate decreases lipid accumulation in diet-induced nonalcoholic fatty liver disease mouse model. Mol. Pharm. 83, 648-658.

Yamazaki, Y., Zhao, N., Caulfield, T.R., Liu, C.-C., Bu, G., 2019. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat. Rev. Neurol. 15, 501-518.

Yang, C., McDonald, J.G., Patel, A., Zhang, Y., Umetani, M., Xu, F., Westover, E.J., Covey, D.F., Mangelsdorf, D.J., Cohen, J.C., Hobbs, H.H., 2006. Sterol intermediates from cholesterol synthetic pathway as liver X receptor ligands. J. Biol. Chem. 281, 27816-27826.

Yang, J., Liu, L., Yang, X., Duan, Y., Zeng, P., Yang, S., Ma, C., Li, X., Han, J., Chen, Y., 2020. Combination of MEK1/2 inhibitor and LXR ligand synergistically inhibit atherosclerosis in LDLR deficient mice. Biochem. Biophys. Res. Commun. 522, 512-517.

Yap, F., Craddock, L., Yang, J., 2011. Mechanism of AMPK suppression of LXR-dependent Srebp-1c transcription. Int. J. Biol. Sci. 7, 645-650.

Zaidi, M., Kim, S.M., Mathew, M., Korkmaz, F., Sultana, F., Miyashita, S., Gumerova, A. A., Frolinger, T., Moldavski, O., Barak, O., Pallapati, A., Rojekar, S., Caminis, J., Ginzburg, Y., Ryu, V., Davies, T.F., Lizneva, D., Rosen, C.J., Yuen, T., 2023. Bone circuitry and interorgan skeletal crosstalk. Life 12.

Zelcer, N., Tontonoz, P., 2006. Liver X receptors as integrators of metabolic and inflammatory signaling. J. Clin. Invest. 116, 607-614.

Zhang, H., Wang, J., Sun, J., Wang, Q., Guo, L., Xu, J., 2023a. 2023a. Regulatory mechanism underlying liver X receptor effects on the tumor microenvironment, inflammation and tumorigenesis. Expert Opin. Ther. Targets 20, 989-998.

Zhang, L., Yan, F., Zhang, S., Lei, D., Charles, M.A., Cavigniolio, G., Oda, M., Krauss, R.M., Weisgraber, K.H., Rye, K.-A., Pownall, H.J., Qiu, X., Ren, G., 2012a. Structural basis of transfer between lipoproteins by cholesteryl ester transfer protein. Nat. Chem. Biol. 8, 342-349.

Zhang, R., Dong, Y., Liu, Y., Moezzi, D., Ghorbani, S., Mirzaei, R., Lozinski, B.M., Dunn, J.F., Yong, V.W., Xue, M., 2023b. Enhanced liver X receptor signalling reduces brain injury and promotes tissue regeneration following experimental intracerebral haemorrhage: roles of microglia/macrophages. Stroke Vasc. Neurol. 8, 486-502.

Zhang, R., Wuerch, E., Yong, V.W., Xue, M., 2024. LXR agonism for CNS diseases: promises and challenges. J. Neuroinflamm. 21, 97.

Zhang, Y., Breevoort, S.R., Angdisen, J., Fu, M., Schmidt, D.R., Holmstrom, S.R., Kliewer, S.A., Mangelsdorf, D.J., Schulman, I.G., 2012b. Liver LXRalpha expression is crucial for whole body cholesterol homeostasis and reverse cholesterol transport in mice. J. Clin. Invest. 122, 1688-1699.

Zhang, Z., Tang, S., Gui, W., Lin, X., Zheng, F., Wu, F., Li, H., 2020. Liver X receptor activation induces podocyte injury via inhibiting autophagic activity. J. Physiol. Biochem. 76, 317-328.

Zhao, H., Ji, Q., Zhang, W., Wang, S., Ren, J., Yan, K., Wang, Z., Hu, J., Chu, Q., Hu, H., Cai, Y., Wang, Q., Huang, D., Ji, Z., Li, J., Belmonte, J.C.I., Song, M., Zhang, W., Qu, J., Liu, G.H., 2022. Destabilizing heterochromatin by APOE mediates senescence. Nat. Aging 2, 303-316.
Zhu, L., Bakovic, M., 2008. Liver X receptor agonists inhibit the phospholipid regulatory gene CTP: phosphoethanolamine cytidylyltransferase-Pcyt2. Res Lett. Biochem. 2008, 801849.

Zitzer, H., Wente, W., Brenner, M.B., Sewing, S., Buschard, K., Gromada, J., Efanov, A. M., 2006. Sterol regulatory element-binding protein 1 mediates liver X receptor-

beta-induced increases in insulin secretion and insulin messenger ribonucleic acid levels. Endocrinology 147, 3898-3905.

Zuercher, W.J., Buckholz, R.G., Campobasso, N., Collins, J.L., Galardi, C.M., Gampe, R. T., Hyatt, S.M., Merrihew, S.L., Moore, J.T., Oplinger, J.A., Reid, P.R., Spearing, P.K., Stanley, T.B., Stewart, E.L., Willson, T.M., 2010. Discovery of tertiary sulfonamides as potent liver X receptor antagonists. J. Med. Chem. 53, 3412-3416.