tbuckley/cabot-search huggingface dataset:
TMEM219 signaling promotes intestinal stem cell death and exacerbates colitis
Authors: Francesca D'Addio, Giovanni Amabile, Emma Assi, Anna Maestroni, Adriana Petrazzuolo, Cristian Loretelli, Ahmed Abdelasalam, Moufida Ben Nasr, Ida Pastore, Maria Elena Lunati, Vera Usuelli, Monica Zocchi, Andy Joe Seelam, Domenico Corradi, Stefano La Rosa, Virna Marin, Monique Zangarini, Marta Nardini, Stefano Porzio, Filippo Canducci, Claudia Nardini, Basset El Essawy, Manuela Nebuloni, Jun Yang, Massimo Venturini, Giovanni Maconi, Franco Folli, Silvio Danese, Gianvincenzo Zuccotti, Gianluca M Sampietro, Sandro Ardizzone, Paolo Fiorina
Journal: Journal of Clinical Investigation (2025)

Mechanisms by which mucosal regeneration is abrogated in inflammatory bowel disease (IBD) are still under investigation, and a role for an intestinal stem cell (ISC) defect is now emerging. Herein, we report an abnormal ISC death that occurs in Crohn's disease, which exacerbates colitis, limits ISC-dependent mucosal repair, and is controlled through the death factor Transmembrane protein 219 (TMEM219). Large alterations in TMEM219 expression were observed in patients with Crohn's disease, particularly in those with active disease and/or those who were nonresponders to conventional therapy, confirming that TMEM219 signaling is abnormally activated and leads to failure of the mucosal regenerative response. Mechanistic studies revealed a proapoptotic TMEM219-mediated molecular signature in Crohn's disease, which associates with Caspase-8 activation and ISC death. Pharmacological blockade of the IGFBP3/TMEM219 binding/signal with the recombinant protein ecto-TMEM219 restored the self-renewal abilities of miniguts generated from patients with Crohn's disease in vitro and ameliorated DSS-induced and T cell-mediated colitis in vivo, ultimately leading to mucosal healing. Genetic tissue-specific deletion of TMEM219 in ISCs in newly generated TMEM219fl/flLGR5cre mice revived their mucosal regenerative abilities both in vitro and in vivo. Our findings demonstrate that a TMEM219-dependent ISC death exacerbates colitis and that TMEM219 blockade reestablishes intestinal self-renewal properties in IBD.
Inhibition of DNAJ-HSP70 interaction improves strength in muscular dystrophy
Authors: Rocio Bengoechea, Andrew R. Findlay, Ankan K. Bhadra, Hao Shao, Kevin C. Stein, Sara K. Pittman, Jil A.W. Daw, Jason E. Gestwicki, Heather L. True, Conrad C. Weihl
Journal: Journal of Clinical Investigation (2025)
Endothelial dysfunction in patients with type 2 diabetes: the truth is in the blood
Authors: Sarah Costantino, Shafeeq A Mohammed, Francesco Paneni
Journal: Journal of Clinical Investigation (2025)

Endothelial dysfunction remains a cornerstone of diabetic vascular complications. RBCs emerge as pivotal players in endothelial dysfunction, yet the underlying mechanisms remain elusive. In this issue of the JCI, Collado et al. show that the detrimental action of RBCs on the endothelium is mediated by extracellular vesicles (EVs). EVs derived from RBCs (RBC-EVs) of patients with diabetes were taken up by the endothelium and were able to impair endothelium-dependent relaxation via an EV-mediated transfer of the prooxidant enzyme arginase-1 (Arg1) from RBCs to endothelial cells. These findings reveal events implicated in vascular oxidative stress and set the stage for personalized approaches preventing RBC-EVs' uptake by the endothelium.
Traffic jam in lung capillaries: inter-organ communication impedes gas exchange after acute kidney injury
Authors: Ulrich Matt, Susanne Herold
Journal: Journal of Clinical Investigation (2025)

Acute kidney injury (AKI) is a frequent complication in critically ill patients and triggers a systemic inflammatory response that can contribute to lung injury, ultimately worsening clinical outcomes. However, diagnostic and therapeutic strategies remain unavailable. In this issue of the JCI, Komaru et al. explored leukocyte trafficking and vascular pooling following AKI in mice as an underlying mechanism of acute lung injury. Using intravital microscopy, the authors observed rapid accumulation of neutrophils in pulmonary capillaries within minutes of AKI onset. These neutrophils followed monocytes and slowed blood flow. Notably, disruption of this process improved oxygenation. The findings provide insights into this complex inter-organ crosstalk and open avenues for future research.
EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis
Authors: Haizhong Feng, Giselle Y. Lopez, Chung Kwon Kim, Angel Alvarez, Christopher G. Duncan, Ryo Nishikawa, Motoo Nagane, An-Jey A. Su, Philip E. Auron, Matthew L. Hedberg, Lin Wang, Jeffery J. Raizer, John A. Kessler, Andrew T. Parsa, Wei-Qiang Gao, Sung-Hak Kim, Mutsuko Minata, Ichiro Nakano, Jennifer R. Grandis, Roger E. McLendon, Darell D. Bigner, Hui-Kuan Lin, Frank B. Furnari, Webster K. Cavenee, Bo Hu, Hai Yan, Shi-Yuan Cheng
Journal: Journal of Clinical Investigation (2025)
Disease classification, diagnostic challenges, and evolving clinical trial design in MASLD
Authors: Mette Munk Lauridsen, Kim Ravnskjaer, Lise Lotte Gluud, Arun J Sanyal
Journal: Journal of Clinical Investigation (2025)

Metabolic dysfunction-associated steatotic liver disease (MASLD) diagnosis and management have evolved rapidly alongside the increasing prevalence of obesity and related complications. Hepatology has expanded its focus beyond late-stage cirrhosis and portal hypertension to earlier, complex MASLD cases in younger patients, necessitating closer collaboration with endocrinology. The renaming of nonalcoholic fatty liver disease (NAFLD) to MASLD reflects its pathophysiology, reduces stigma, and has prompted new research directions. Noninvasive tests such as liver stiffness measurement now play a crucial role in diagnosis, reducing reliance on invasive liver biopsies. However, advanced omics technologies, despite their potential to enhance diagnostic precision and patient stratification, remain underutilized in routine clinical practice. Behavioral factors, including posttraumatic stress disorder (PTSD) and lifestyle choices, influence disease outcomes and must be integrated into patient management strategies. Primary care settings are critical for early screening to prevent progression to advanced disease, yet sizable challenges remain in implementing effective screening protocols. This Review explores these evolving aspects of MASLD diagnosis and management, emphasizing the need for improved diagnostic tools, multidisciplinary collaboration, and holistic care approaches to address existing gaps and ensure comprehensive patient care across all healthcare levels.
GALNT14 deficiency: connecting multiple links in the IgA nephropathy pathogenetic chain
Authors: John Pell, Madhav C. Menon
Journal: Journal of Clinical Investigation (2025)

IgA nephropathy (IgAN) is a highly prevalent type of primary glomerulonephritis. IgAN involves mesangial deposition of immune complexes leading to complement activation, inflammation, and glomerular injury. A key hit for pathogenesis involves aberrant O-glycosylation in the hinge region of IgA. Despite its prevalence, however, the mechanisms underlying IgAN remain incompletely understood. In this issue of the JCI, Prakash and colleagues used whole-exome sequencing of two IgAN probands to identify loss-of-function variants in GALNT14 leading to loss of the enzyme GalNAc-T14, which is involved in O-glycosylation. The authors then performed a classical bedside-to-bench investigation using a Galnt14-/- mouse model and connected loss of GalNAc-T14 to excess IgA production, impaired B lymphocyte homing, and defective intestinal mucus production. These findings build a more unified understanding of IgAN pathogenesis from defective O-glycosylation with loss-of-function variants in GALNT14.
Promoting mucosal healing by targeting TMEM219-dependent intestinal epithelial stem cell defects in inflammatory bowel disease
Authors: Nicolas Schlegel
Journal: Journal of Clinical Investigation (2025)

Inflammatory Bowel Diseases (IBD), including Crohn's disease and ulcerative colitis, pose challenges due to their complex pathophysiology and high prevalence. Despite advances in immune-targeted therapies, a substantial number of patients fail to achieve mucosal healing, highlighting the need for alternative therapeutic strategies. In this issue of the JCI, D'Addio et al. identified another mechanism underlying impaired epithelial regeneration in Crohn's disease. They found that abnormal cell death in intestinal epithelial stem cells, mediated by altered TMEM219 signaling, led to impaired mucosal healing. Targeting TMEM219 with ecto-TMEM219, which blocks its activation, restored stem cell function and promoted mucosal healing in vitro and in vivo. These findings suggest a promising therapeutic avenue focusing on epithelial repair. Additionally, patient-derived organoids (PDOs) emerge as a valuable tool for personalized treatment strategies and for advancing the field of IBD research. This study underscores the importance of epithelial cell biology in developing innovative IBD therapies.
AgRP neuron hyperactivity drives hyperglycemia in a mouse model of type 2 diabetes
Authors: Yang Gou, Micaela Glat, Vincent Damian, Caeley L Bryan, Bao Anh Phan, Chelsea L Faber, Arikta Trivedi, Matthew K Hwang, Jarrad M Scarlett, Gregory J Morton, Michael W Schwartz
Journal: Journal of Clinical Investigation (2025)

Growing evidence suggests that the pathogenesis of type 2 diabetes (T2D) involves dysfunctional central mechanisms, and, hence, the brain can be targeted to treat this disease. As an example, a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) can normalize hyperglycemia for weeks or months in rodent models of T2D. Convergent evidence implicates inhibition of a particular subset of neurons as a mediator of this FGF1 effect. Specifically, AgRP neurons, which are located in the hypothalamic arcuate nucleus (ARC) and are hyperactive in Lepob/ob mice and other rodent models of T2D. To investigate whether chronic AgRP neuron inactivation mimics the antidiabetic action of FGF1, we directed an adeno-associated virus (AAV) containing a cre-inducible tetanus toxin-GFP (TeTx-GFP) cassette (or cre-inducible AAV GFP control) to the ARC of obese, diabetic male Lepob/ob mice in which cre recombinase is expressed solely by AgRP neurons (Lepob/ob AgRP-Cre mice). We report that over a 10-wk period of observation, hyperglycemia was fully normalized by AgRP neuron inactivation. In contrast, changes in energy homeostasis parameters (food intake, energy expenditure, body weight, and fat mass) were not observed. We conclude that in diabetic male Lepob/ob mice, AgRP neuron hyperactivity is required for hyperglycemia but is dispensable for obesity.
IL-32–producing CD8+ memory T cells define immunoregulatory niches in human cutaneous leishmaniasis
Authors: Nidhi S Dey, Shoumit Dey, Naj Brown, Sujai Senarathne, Luiza Campos Reis, Ritika Sengupta, Jose Al Lindoso, Sally R James, Lesley Gilbert, Dave Boucher, Mitali Chatterjee, Hiro Goto, Shalindra Ranasinghe, Paul M Kaye
Journal: Journal of Clinical Investigation (2025)

Human cutaneous leishmaniasis (CL) is characterized by chronic skin pathology. Experimental and clinical data suggest that immune checkpoints (ICs) play a crucial role in disease outcome, but the cellular and molecular niches that facilitate IC molecule expression during leishmaniasis are ill defined. In Sri Lankan patients with CL, indoleamine 2,3-dioxygenase 1 (IDO1) and programmed death-ligand 1 (PD-L1) were enriched in skin lesions, and reduced PD-L1 expression early after treatment initiation was predictive of a cure rate following antimonial therapy. Here, we used spatial cell interaction mapping to identify IL-32-expressing CD8+ memory T cells and Tregs as key components of the IDO1/PD-L1 niche in Sri Lankan patients with CL and in patients with distinct forms of dermal leishmaniasis in Brazil and India. Furthermore, the abundance of IL-32+ cells and IL-32+CD8+ T cells at treatment initiation was negatively correlated with the rate of cure in Sri Lankan patients. This study provides insights into the spatial mechanisms underpinning IC expression during CL and offers a strategy for identifying additional biomarkers of treatment response.
Safety and efficacy of the selective TYK2/JAK1 inhibitor TLL-018 in moderate-to-severe plaque psoriasis: A phase 1b, randomized, double-blind, placebo-controlled study
Authors: Jia-Qi Chen, Min Zheng, Wen-Hao Yin, Ping Wang, Xiao-Wei Shi, Tie-chi Lei, Zhi-Ming Li, Meng Pan, Yu-Ling Shi, Yu-Zhen Li, Congxin Liang, Xiao-Yong Man
Journal: British Journal of Dermatology (2025)

Abstract Background Psoriasis treatments that provide rapid and extensive itch relief, lesion clearance are inadequate. Objective To evaluate the efficacy and safety of the tyrosine kinase 2/Janus kinase 1 inhibitor TLL-018 in patients with moderate-to-severe psoriasis. Methods This phase 1b, double-blind, placebo-controlled study randomized participants to receive TLL-018 (2:2:2:1) 10:20:30 mg:placebo (12 weeks) twice daily (BID) orally (NCT05342428). The study included 73 patients with moderate-to-severe psoriasis. Eligible patients were aged 18-75 years and were diagnosed with moderate-to-severe psoriasis at least 6 months prior to screening, as defined by a psoriasis area and severity index (PASI) of ≥12, a body surface area (BSA) ≥10%, and a physician’s global assessment (PGA) of ≥3. The primary endpoint was safety of TLL-018. The efficacy endpoints were proportions of patients achieving a PASI 75, PGA of 0 or 1, and DLQI 0/1 at week 12. Results A total of 73 participants were treated. TLL-018 was well tolerated, and most treatment-emergent adverse events were mild/moderate. At week 12, 40.0% (8 of 20 patients) of the patients achieved PASI 75 with TLL-018 10 mg BID; 47.6% (10 of 21 patients), with 20 mg BID; 61.9% (13 of 21 patients), with 30 mg BID; and 9.1% (1 of 11 patients), with placebo. The PGA 0/1 were 35%, 42.9%, 71.4% and 0%, respectively. 10 of 21 patients (47.6%) in TLL-018 30 mg BID group achieved PASI 90. Conclusions TLL-018 was well tolerated and showed promising efficacy at week 12 comparing placebo in patients with moderate-to-severe plaque psoriasis.
Ubiquitin-conjugating enzyme UBE2N modulates proteostasis in immunoproteasome-positive acute myeloid leukemia
Authors: Chiharu Ishikawa, Laura Barreyro, Avery M Sampson, Kathleen M Hueneman, Kwangmin Choi, Sophia Y Philbrook, Issac Choi, Lyndsey C Bolanos, Mark Wunderlich, Andrew G Volk, Stephanie S Watowich, Kenneth D Greis, Daniel T Starczynowski
Journal: Journal of Clinical Investigation (2025)

Altered protein homeostasis through proteasomal degradation of ubiquitinated proteins is a hallmark of many cancers. Ubiquitination, coordinated by E1, E2, and E3 enzymes, involves up to 40 E2-conjugating enzymes in humans to specify substrates and ubiquitin linkages. In a screen for E2 dependencies in acute myeloid leukemia (AML), ubiquitin conjugating enzyme E2 N (UBE2N) emerged as the top candidate. To investigate UBE2N's role in AML, we characterized an enzymatically defective mouse model of UBE2N, revealing UBE2N's requirement in AML without an impact on normal hematopoiesis. Unlike other E2s, which mediate lysine-48 (K48) polyubiquitination and degradation of proteins, UBE2N primarily synthesizes K63-linked chains, stabilizing or altering protein function. Proteomic analyses and a whole-genome CRISPR-activation screen in pharmacologically and genetically UBE2N-inhibited AML cells unveiled a network of UBE2N-regulated proteins, many of which are implicated in cancer. UBE2N inhibition reduced their protein levels, leading to increased K48-linked ubiquitination and degradation through the immunoproteasome and revealing UBE2N activity is enriched in immunoproteasome-positive AML. Furthermore, an interactome screen identified tripartite motif-containing protein 21 (TRIM21) as the E3 ligase partnering with activated UBE2N in AML to modulate UBE2N-dependent proteostasis. In conclusion, UBE2N maintains proteostasis in AML by stabilizing target proteins through K63-linked ubiquitination and prevention of K48 ubiquitin-mediated degradation by the immunoproteasome. Thus, inhibition of UBE2N catalytic function suppresses leukemic cells through selective degradation of critical proteins in immunoproteasome-positive AML.
ST6GalNAc-I regulates tumor cell sialylation via NECTIN2/MUC5AC-mediated immunosuppression and angiogenesis in non–small cell lung cancer
Authors: Muthamil Iniyan Appadurai, Sanjib Chaudhary, Ashu Shah, Gopalakrishnan Natarajan, Zahraa W Alsafwani, Parvez Khan, Dhananjay D Shinde, Subodh M Lele, Lynette M Smith, Mohd Wasim Nasser, Surinder Kumar Batra, Apar Kishor Ganti, Imayavaramban Lakshmanan
Journal: Journal of Clinical Investigation (2025)

Glycosylation controls immune evasion, tumor progression, and metastasis. However, how tumor cell sialylation regulates immune evasion remains poorly characterized. ST6GalNAc-I, a sialyltransferase that conjugates sialic acid to the glycans in glycoproteins, was overexpressed in an aggressive-type KPA (KrasG12D/+ Trp53R172H/+ Ad-Cre) lung adenocarcinoma (LUAD) model and patient samples. Proteomic and biochemical analysis indicated that ST6GalNAc-I mediated NECTIN2 sialylation in LUAD cells. ST6GalNAc-I-deficient tumor cells cocultured with T cells were more susceptible to T cell-mediated tumor cell killing, indicating a key role for NECTIN2 in T cell dysfunction. Mice injected with St6galnac-I-knockdown syngeneic cells showed reduced lung tumor incidence and Nectin2/Tigit-associated immunosuppression. ST6GalNAc-I-deficient cells exhibited reduced P-DMEA metabolite levels, while administration of P-DMEA promoted LUAD cell proliferation via MUC5AC. MUC5AC interacted and colocalized with PRRC1 in the Golgi, suggesting a potential role for PRRC1 in MUC5AC glycosylation. Mice injected with ST6GalNAc-I/MUC5AC-deficient cells (human LUAD) exhibited reduced lung tumor incidence, angiogenesis, and liver metastases. Mechanistically, ST6GalNAc-I/MUC5AC regulates VCAN-V1, a key factor in tumor matrix remodeling during angiogenesis and metastasis. These findings demonstrate that ST6GalNAc-I-mediated sialylation of NECTIN2/MUC5AC is critical for immune evasion and tumor angiogenesis. Targeting this pathway may prevent LUAD development and/or metastasis.
MEK1/2 inhibitors suppress pathological α-synuclein and neurotoxicity in cell models and a humanized mouse model of Parkinson’s disease
Authors: Huilan Wang, Qing Wang, Haoxiang Xu, Yuanzheng Wu, Siulam Cheung, Qianhui Xu, Chengfang Pan, Jingyu Cao, Zhiyuan Cao, Ruonan Yang, Yu Ding, Yiyan Fei, Yongfeng Chen, Jian Wang, Cong Liu, Boxun Lu
Journal: Science Translational Medicine (2025)

The abnormal accumulation of misfolded proteins is a common hallmark of many neurodegenerative disorders. Among these proteins, α-synuclein (αsyn) is a well-characterized pathogenic protein in Parkinson’s disease (PD) and other synucleinopathies. αsyn can be hyperphosphorylated and form pathological aggregates, leading to neurodegeneration. Thus, chemical modulators of pathological αsyn may suppress its downstream toxicity and provide entry points to therapeutic intervention. Here, we identified mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitors as negative modulators of basal αsyn in wild-type cells and that pathological αsyn in αsyn preformed fibrils (αsyn-PFF) induced the neuroblastoma cell line SHSY-5Y, PC12 cells, and primary cultured neurons. We further demonstrated that these inhibitors suppressed Ser 129 phosphorylated αsyn (p-αsyn) through the kinase PLK2 downstream of MEK1/2-ERK2 in PD cell models. We established a humanized PD mouse model by injecting human αsyn-PFF into mice with homozygous knock-in of human SNCA . Oral administration of blood-brain barrier–penetrable MEK1/2 inhibitors lowered pathological αsyn and rescued PD-relevant phenotypes with an acceptable safety profile in these mice. Collectively, these data highlight MEK1/2 inhibitors as a potential therapeutic strategy for PD.
Asparagine endopeptidase cleaves apolipoprotein A1 and accelerates pathogenesis of atherosclerosis
Authors: Mengmeng Wang, Bowei Li, Shuke Nie, Xin Meng, Guangxing Wang, Menghan Yang, Wenxin Dang, Kangning He, Tucheng Sun, Ping Xu, Xifei Yang, Keqiang Ye
Journal: Journal of Clinical Investigation (2025)

Atherosclerosis is a slowly progressing inflammatory disease characterized with cholesterol disorder and intimal plaques. Asparagine endopeptidase (AEP) is an endolysosomal protease that is activated under acidic conditions and is elevated substantially in both plasma and plaques of patients with atherosclerosis. However, how AEP accelerates atherosclerosis development remains incompletely understood, especially from the view of cholesterol metabolism. This project aims to reveal the crucial substrate of AEP during atherosclerosis plaque formation and to lay the foundation for developing novel therapeutic agents for Atherosclerosis. Here, we show that AEP is augmented in the atherosclerosis plaques obtained from patients and proteolytically cuts apolipoprotein A1 (APOA1) and impairs cholesterol efflux and high-density lipoprotein (HDL) formation, facilitating atherosclerosis pathologies. AEP is activated in the liver and aorta of apolipoprotein E-null (APOE-null) mice, and deletion of AEP from APOE-/- mice attenuates atherosclerosis. APOA1, an essential lipoprotein in HDL for cholesterol efflux, is cleaved by AEP at N208 residue in the liver and atherosclerotic macrophages of APOE-/- mice. Blockade of APOA1 cleavage by AEP via N208A mutation or its specific inhibitor, #11a, substantially diminishes atherosclerosis in both APOE-/- and LDLR-/- mice. Hence, our findings support that AEP disrupts cholesterol metabolism and accelerates the development of atherosclerosis.
Rapid closure and hemostasis of ruptured soft tissues using a modified human tropoelastin-based sealant in preclinical models
Authors: Mahsa Ghovvati, Saumya Jain, George Z. Cheng, Naoki Kaneko, Joshua A. Boys, Taichiro Imahori, Tess De Maeseneer, Reihaneh Haghniaz, Robert B. Cameron, Anthony S. Weiss, Nasim Annabi
Journal: Science Translational Medicine (2025)

Treatment of injuries to soft elastic organs is often hindered by challenging anatomical features and limitations of existing sealant materials, which may lack adequate tissue adhesion, elasticity, biocompatibility, and effective hemostatic properties. To address these clinical challenges, we developed an injectable elastic sealant formulated with methacryloyl-modified human recombinant tropoelastin (MeTro) and Laponite silicate nanoplatelets (SNs). We optimized the hydrogel formulation for mechanical properties, adhesion, biocompatibility, and hemostatic properties and used visible light for cross-linking to improve safety. MeTro/SN hydrogels had increased tissue adhesion strength and burst pressure in vitro and ex vivo compared with MeTro alone or commercial sealants. The addition of SNs to the hydrogels facilitated faster blood clotting in vitro without increasing hemolysis. Applied to incisional injuries on rat lungs or aortas, MeTro/SN had burst pressures comparable to those of native tissue and greater than those of MeTro after a 7-day in vivo application. On porcine lungs, MeTro/SN also supported effective lung sealing and burst pressure similar to native lung 14 days after injury sealing. In a rodent tail hemostasis model, MeTro/SN reduced bleeding compared with MeTro. In an injured porcine lung model, early hemostasis was better than the tested commercial sealants. The results demonstrated that MeTro/SN provided effective tissue sealing and promoted hemostasis in a time frame that minimized blood loss without causing a major inflammatory response. These findings highlight the translational potential of our engineered sealant with biomimetic mechanics, durable tissue adhesion, and rapid hemostasis as a multipronged approach for the sealing and repair of traumatic injuries to soft organs.