tbuckley/cabot-search huggingface dataset:
Current landscape and future directions of targeted-alpha-therapy for glioblastoma treatment
Authors: Loris Roncali, François Hindré, Edouard Samarut, Franck Lacoeuille, Audrey Rousseau, Jean-Michel Lemée, Emmanuel Garcion, Michel Chérel
Journal: Theranostics (2025)

Glioblastoma (GB) is the most aggressive malignancy of the central nervous system. Despite two decades of intensive research since the establishment of the standard of care, emerging strategies have yet to produce consistent satisfactory outcomes. Because of its specific localisation and intricate characteristics, GB is a uniquely regulated solid tumour with a strong resistance to therapy. Advances in targeted radionuclide therapy (TRT), particularly with the introduction of a-emitting radionuclides, have unveiled potential avenues for the management of GB. Recent preclinical and clinical studies underscored promising advancements for targeted-α-therapy (TAT), but these therapeutic approaches exhibit a vast design heterogeneity, encompassing diverse radionuclides, vectors, target molecules, and administration modalities. This review seeks to critically assess the therapeutic landscape of GB through the perspective of TAT. Here, the focus is made on the advancements and limitations of in vivo explorations, pilot studies, and clinical trials, to determine the best directions for future investigations. In doing so, we hope to identify existing challenges and draw insights that might pave the way towards a more effective therapeutic approach.
FOS-driven inflammatory CAFs promote colorectal cancer liver metastasis via the SFRP1-FGFR2-HIF1 axis
Authors: Long Liu, Yuhao Ba, Shuaixi Yang, Aning Zuo, Shutong Liu, Yuyuan Zhang, Shuqin Xu, Siyuan Weng, Benyu Liu, Peng Luo, Quan Cheng, Jinhai Deng, Hui Xu, Yukang Chen, Chuhan Zhang, Xing Zhou, Yuqing Ren, Xinwei Han, Zhenyu Hou, Zaoqu Liu
Journal: Theranostics (2025)

Rationale: Cancer-associated fibroblasts (CAFs) exhibit diverse functions, yet their roles in colorectal cancer liver metastasis (CRLM) remain poorly understood. Methods: Through integrated analysis of single-cell RNA sequencing and spatial transcriptomics from colorectal cancer patients (CRCP: non-metastatic primary tumors; CRCM: metastatic primary tumors with liver metastases), combined with in vitro and in vivo models to investigate the role of CAFs in CRLM. In vitro experiments included six groups to reveal the role of SFRP1-producing CAFs, comprising PBS (control) and recombinant human SFRP1 (rhSFRP1) treated SW480 cells, PBS (control) and recombinant mouse SFRP1 (rmSFRP1) treated CT26 cells, and conditioned medium (CM) derived from CAF-NC and CAF-Sfrp1 treated CT26 cells. Preclinical models were further employed to elucidate the role of SFRP1 in CRLM. Subcutaneous xenografts models were constructed from PBS (control) and rhSFRP1 treated SW480 cells. For orthotopic tumor metastasis models, CT26 cells were pre-cultured with CAF-NC or CAF-Sfrp1 and then orthotopically injected into BALB/c mice. Results: We identified an inflammatory CAF subtype (CFD+ iCAFs) associated with poor clinical outcomes, advanced staging, and metastasis. Transcriptional regulation analysis revealed FOS-mediated differentiation of CFD+ iCAFs drives SFRP1 overexpression. In vitro and in vivo experiments confirmed that SFRP1-producing CAFs promote tumor stemness and epithelial-mesenchymal transition (EMT). Mechanistically, SFRP1 from CFD+ iCAFs binds FGFR2, activating the HIF1 signaling pathway to enhance tumor stemness, EMT, and CRLM progression. Conclusion: This study highlights CFD+ iCAFs as key regulators of tumor-stromal interactions and identifies SFRP1 as a potential therapeutic target in CRLM.
Targeting USP11 counteracts <i>SFTPC<sup>I73T</sup></i>-associated interstitial lung disease in hiPSCs-derived alveolar organoids and in vivo models
Authors: Janardhan Keshav Karapurkar, Sripriya Rajkumar, Ji-Hye Jung, Ji-Young Kim, Girish Birappa, D A Ayush Gowda, Jencia Carminha Colaco, Bharathi Suresh, Jung-Yun Choi, Sang Hyeon Woo, Won-Jun Jo, Jong-Hee Lee, Kye-Seong Kim, Seok-Ho Hong, Suresh Ramakrishna
Journal: Theranostics (2025)

Background: Interstitial lung disease (ILD) is a pulmonary disorder characterized by a combination of inflammation and fibrosis in the lung parenchyma, which initiates with the dysfunction of alveolar epithelial cells (AECs). The alveolar cells secrete surfactant proteins that lowers the surface tension of fluids in the lungs and maintains the stability of pulmonary tissue. Mutations on surfactant protein C (SFTPC), particularly I73T, are associated with a toxic gain of function that causes misfolding and the accumulation of immature SFTPC proteins, triggering pulmonary fibrosis (PF). Therefore, it is crucial to block the accumulation of the SFTPC I73T protein during ILD progression. Methods: We used a loss-of-function-based CRISPR/Cas9 library kit to screen genome-wide for deubiquitinating enzymes that regulate the SFTPC protein. The interaction between USP11 and SFTPC and its ubiquitination status was validated by immunoprecipitation and the TUBEs assay. HDR-directed knock-in of the I73T mutation into the SFTPC locus in human induced pluripotent stem cells (hiPSCs) was performed using the CRISPR/Cas9 system, and then those cells were differentiated into alveolar organoids (AOs) using a forced aggregation protocol. The clinical relevance of the USP11 inhibitor and its effect on preventing PF were investigated in a TGF-β-induced fibrosis in AOs and bleomycin (BLM)-induced mouse model. Results: We identified USP11 as a novel deubiquitinase that interacts with, stabilizes, deubiquitinates, and extends the half-life of SFTPC. Remarkably, USP11 stabilized and prolonged the half-life of the SFTPC I73T mutant protein significantly more than the wild type. In vitro functional studies revealed that USP11 exacerbates SFTPC I73T -induced fibrosis and enhances the epithelial-to-mesenchymal transition. Furthermore, we present a human in vitro model for investigating SFTPCI73T -induced fibrosis: hiPSCs-derived-AOs carrying the pathogenic SFTPCI73T variant. Interestingly, USP11 depletion in the organoids mitigated SFTPC I73T -induced fibrosis. Finally, pharmacological inhibition of USP11 prevented PF caused by TGF-β in hiPSCs-SFTPCI73T-AOs and BLM-induced mouse model, underscoring its therapeutic potential. Conclusions: Altogether, USP11 is a major protein stabilizer of SFTPC, and the clinical inhibition of USP11 during PF could be a novel therapeutic approach for ILD patients.
EphA2-targeted alpha-particle theranostics for enhancing PDAC treatment
Authors: Ajay Kumar Sharma, Kuldeep Gupta, Akhilesh Mishra, Gabriela Lofland, Sophia Y Chen, Ian Marsh, Peyton T Fair, Robert F Hobbs, Todd M Armstrong, Elizabeth M Jaffee, Edward W Gabrielson, Lei Zheng, Sridhar Nimmagadda
Journal: Theranostics (2025)

Background: Pancreatic ductal adenocarcinoma (PDAC) presents a formidable challenge in oncology due to its aggressive nature and resistance to therapy. Current treatments, including surgery, chemotherapy, and radiotherapy, have limited success in improving patient outcomes. This study addresses the urgent need for novel radiotheranostic strategies for PDAC by investigating EphA2 as a potential target. Methods and Results: Analysis of genomic data from the Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Atlas (TCGA) revealed elevated EphA2 expression in PDAC, confirmed by immunohistochemical staining of tumor tissue microarrays (TMAs). Further analysis showed variable EphA2 expression across PDAC cell lines, with surface receptor density not always correlating with mRNA levels. A low molecular weight peptide was developed and labeled with gallium-68 for PET imaging. In vitro studies demonstrated specific binding to EphA2-expressing PDAC cells with rapid internalization. In vivo PET imaging in subcutaneous and orthotopic PDAC models confirmed high tumor uptake and minimal off-target binding, confirming EphA2 as a valid imaging target. For molecular radiotherapy, a DOTA-conjugated peptide was labeled with the alpha-particle emitter, actinium-225. In vitro studies revealed dose-dependent cytotoxicity in PDAC cells, with an IC50 of 0.32 µCi/mL. In a tumor model, treatment with Ac-225 labeled peptide significantly inhibited tumor growth compared to controls, with mild adverse effects. Conclusion: These results establish EphA2 as a promising radiotheranostic target in PDAC, with potential for both non-invasive imaging and targeted radiotherapy. Given the potential, further optimization of EphA2-targeted agents are warranted to advance personalized treatment strategies for PDAC patients.
PD-1 activation mitigates lupus nephritis by suppressing hyperactive and heterogeneous PD-1<sup>+</sup>CD8<sup>+</sup> T cells
Authors: Jun Deng, Junling Zhu, Xiaoyue Jiang, Chao Yao, Haifeng Chen, Yanjie Ding, Peng Niu, Qian Chen, Huihua Ding, Nan Shen
Journal: Theranostics (2025)

Rationale: Programmed cell death protein 1 (PD-1)-expressing CD8+ T cells are typically associated with exhaustion in cancer and infections, but their role in autoimmune diseases, particularly lupus nephritis (LN), remains less understood. Understanding the characteristics and functions of PD-1+CD8+ T cells in LN could help identify novel therapeutic strategies. Methods: We analyzed the abundance and phenotypes of PD-1+CD8+ T cells in LN patients and NZB/W F1 mice. Single-cell RNA sequencing (scRNA-seq) was used to delineate subsets and TCR clonal diversity in PD-1+CD8+ T cells in NZB/W F1 mice. The therapeutic efficacy of a PD-L1 Fc fusion protein on kidney pathology and proteinuria in NZB/W F1 mice was evaluated. In addition, the inhibitory mechanism of PD-1 in CD8+ T cells were further explored using RNA-seq, q-PCR, flow cytometry, and Western blot. Results: PD-1+CD8+ T cells were enriched in LN patients and NZB/W F1 mice, exhibiting elevated activation markers and cytotoxic molecules compared to PD-1- cells. scRNA-seq identified seven distinct subsets with diverse effector functions and robust TCR clonal expansion in the kidney of NZB/W F1 mice with severe disease. PD-L1 Fc treatment reduced kidney damage and proteinuria in NZB/W F1 mice, which correlated with decreased frequencies of PD-1+CD8+ and IFN-γ+CD8+ T cells. Mechanistically, PD-L1 Fc inhibited Stat1 phosphorylation, T-bet expression, and IFN-γ production in CD8+ T cells. Conclusion: These findings show that PD-1+CD8+ T cells in LN are hyperactive, clonally expanded, and contribute to disease progression. Targeting the PD-1/PD-L1 pathway with PD-L1 Fc effectively reduced kidney pathology in a murine model of LN, underscoring the potential of modulating PD-1 signaling as a treatment strategy for LN.
<i>In vivo</i> spatiotemporal mapping of proliferation activity in gliomas via water-exchange dynamic contrast-enhanced MRI
Authors: Ruiliang Bai, Yinhang Jia, Bao Wang, Zejun Wang, Guangxu Han, Lijun Liang, Lin Chen, Yang Ming, Guidong Zhu, Yi-Cheng Hsu, Peng Zhao, Yi Zhang, Zhiqiang Liu, Chong Liu, Zhaoqing Li, Yingchao Liu
Journal: Theranostics (2025)

Proliferation activity mapping is crucial for the guidance of first biopsy and treatment evaluation of gliomas due to the highly heterogenous nature of glioma tumor. Here we propose and demonstrate an ease-of-use way of in vivo spatiotemporal mapping of proliferation activity by simply tracking transmembrane water dynamics with magnetic resonance imaging (MRI). Specifically, we demonstrated that proliferation activity can accelerate the transmembrane water transport in glioma cells. Method: The transmembrane water-efflux rate (k io) measured by water-exchange dynamic contrast-enhanced (DCE) MRI. Immunofluorescence, immunohistochemistry, and immunocytochemistry staining were used to validate results obtained from the in vivo imaging studies. Results: In glioma cell cultures, k io precisely followed the dynamic changes of proliferation activity in growth cycles and response to temozolomide (TMZ) treatment. In both animal glioma model and human glioma, k io linearly and strongly correlated with the spatial heterogeneity of intra-tumoral proliferation activity. More importantly, proliferation activity predicted by the single MRI parameter k io is much more accurate than those predicted by state-of-the-art methods using multimodal standard MRIs and advanced machine learning. Upregulated aquaporin 4 (AQP4) expression were observed in most proliferating glioma cells and the knockout of AQP4 could largely slow down proliferation activity, suggesting AQP4 is the potential molecule connecting MRI-k io with proliferation activity. Conclusion: This study provides an ease-of-use, accurate, and non-invasive imaging method for the spatiotemporal monitoring of proliferation activity in glioma.
A new nano-encapsulated TSPO ligand reduces neuroinflammation and improves cognitive functions in Alzheimer's disease model
Authors: Antonella Casamassa, Paola Brancaccio, Virginia Campani, Angela Corvino, Serenella Anzilotti, Giovanni Pecoraro, Giorgia Andreozzi, Raffaella Daniele, Ilaria Piccialli, Anna Pannaccione, Pierluigi Reveglia, Lucia Lecce, Carmela Paolillo, Ferdinando Fiorino, Giuseppe De Rosa, Giuseppe Caliendo, Lucio Annunziato, Giuseppe Pignataro
Journal: Theranostics (2025)

Rationale: The translocator protein 18 kDa (TSPO) is mainly expressed on the outer mitochondrial membrane and is implicated in inflammation, cell survival, and proliferation. TSPO expression in activated microglia is upregulated in Alzheimer's disease (AD), representing both a biomarker and therapeutic target for neuroinflammation. Methods: We synthesized a new TSPO ligand, TEMNAP, a hybrid of temazepam, a compound well known for its ability to bind TSPO, and naproxen, a drug with anti-inflammatory properties that is potentially useful to mitigate neuroinflammation. TEMNAP was encapsulated in a self-assembling nanoparticle transferrin-targeted (SANP-TF-TEMNAP) for brain delivery. The effectiveness of TEMNAP in mitigating inflammatory processes and cognitive behavior was investigated in genetically modified Tg2576 mice, a model of Alzheimer's disease. Its effect on neuroinflammation has also been explored in lipopolysaccharide-activated BV2 microglial cells. Results: SANP-TEMNAP significantly reduced the expression of proinflammatory markers in activated microglia, and this effect was abrogated by TSPO silencing. More importantly, TEMNAP was mass-spectrometrically detected in the hippocampus and cortex of Tg2576 mice after SANP-TF-TEMNAP intraperitoneal administration, preventing hippocampal neuroinflammation and improving cognitive function. Conclusions: These results emphasize the following: (i) the role of transferrin-conjugated self-assembling nanoparticles (SANP-TF) as CNS nanovectors, and (ii) the potential therapeutic effectiveness of peripherally administered SANP-TF-TEMNAP in preventing neuroinflammation associated with cognitive decline.
Neutrophil hitchhiking liposomal drugs for starvation therapy in endometriosis
Authors: Mengni Zhou, Ying Wang, Caihua Li, Jinfu Li, Renbin Dou, Huanhuan Jiang, Yunjiao Zhang, Dawei Chen, Jiqian Zhang, Shasha Zhu
Journal: Theranostics (2025)

Rationale: Endometriosis, characterized by the presence of ectopic endometrial-like tissue, is a common chronic inflammatory disorder in gynecology. However, current treatments, including surgery and hormone therapy, often yield suboptimal outcomes and significant adverse effects. The lack of a drug delivery system specifically targeting ectopic lesions remains a major barrier to the development of more effective treatments. Methods: To exploit the continuous recruitment of neutrophils and elevated reactive oxygen species (ROS) levels within endometriotic lesions, we designed a ROS-responsive liposome (cLipo) modified with neutrophil-targeting peptides on its surface. A minimally invasive mouse model of endometriosis was used to assess the neutrophil-mediated delivery of cLipo. Additionally, we co-loaded the glucose analog 2-deoxy-D-glucose (2-DG) and the autophagy inhibitor chloroquine (CQ) into the liposomes, resulting in the formulation termed cLipo-DC. The therapeutic efficacy of cLipo-DC was evaluated using human endometriotic cells (12Z), endometrial cancer cells (Ishikawa), and an endometriosis mouse model. Results: Although neutrophil hitchhiking strategies are rarely reported in chronic inflammatory diseases, we found that cLipo specifically bound to neutrophils and accumulated in ectopic lesions following intraperitoneal injection in the endometriosis mouse model. Subsequently, in vitro experiments showed that cLipo-DC effectively inhibited glycolysis and autophagy in both 12Z and Ishikawa cells, resulting in cell death. Furthermore, in vivo administration of cLipo-DC in the endometriosis mouse model exerted a significant anti-endometriosis effect, with no detectable side effects. Conclusions: This study provides a novel neutrophil hitchhiking platform for non-hormonal treatment of endometriosis.
Targeting formyl peptide receptor 2 to suppress neuroinflammation in neuromyelitis optica spectrum disorder
Authors: Caiyun Qi, Hongying Hao, Wei Zhang, Yiwei Fu, Yali Han, Jinyi Li, Lixiang Chen, Guiyun Cui, Qing Liu, Yuan Li, Xiaozhen Wang, Ming-Wei Wang, Qiang Liu
Journal: Theranostics (2025)

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an antibody-mediated neurological inflammatory disease. As a G protein-coupled receptor, formyl peptide receptor 2 (FPR2) orchestrates innate and adaptive immunity. Yet the precise role of FPR2 in neuroinflammation is poorly understood. Methods: Peripheral blood samples were collected from patients with NMOSD and healthy controls. Single-cell RNA sequencing (scRNA-seq) and flow cytometry were employed to assess the expression of FPR2 in immune cell subsets. We used a mouse model of NMOSD to examine the therapeutic potential and underlying immune mechanisms of an FPR2 antagonist Quin-C7. MRI and immunostaining were performed to quantify central nervous system injury. Results: ScRNA-seq and flow cytometry analyses revealed that FPR2 was expressed in various myeloid and lymphoid cell types in patients with NMOSD and a mouse model of NMOSD. In NMOSD mice, mouse formyl peptide receptor 2 (mFpr2) was mainly upregulated in microglia. Administration of Quin-C7 led to reduced brain lesion volume, astrocyte loss and demyelination in NMOSD mice. Further, FPR2 antagonism reduced the inflammatory activity of microglia and lymphocyte infiltration into the brain. Notably, depletion of microglia using a CSF1R inhibitor diminished the protective effects of FPR2 antagonism, suggesting that microglia contribute to the benefit of FPR2 antagonism in NMOSD. In contrast, genetic deficiency of T and B cells or antibody depletion of NK cells did not affect the benefit of FPR2 antagonism. Conclusion: Collectively, our findings revealed a previously unrecognized role of FPR2/mFpr2 in control of microglia activity during neuroinflammation, implying that FPR2 antagonism may serve as a viable therapeutic approach to restrict detrimental neuroinflammation and warrant further investigation.
AIG1 protects against doxorubicin-induced cardiomyocyte ferroptosis and cardiotoxicity by promoting ubiquitination-mediated p53 degradation
Authors: Yuekai Shi, Jieru Cai, Lu Chen, Hao Cheng, Xiaoyue Song, Junqiang Xue, Rende Xu, Jianying Ma, Junbo Ge
Journal: Theranostics (2025)

Background: Doxorubicin (DOX) is a widely employed chemotherapeutic drug, while its clinical use is limited by the lethal cardiotoxicity. Previous studies highlighted the critical role of cardiomyocyte ferroptosis in the pathogenesis of DOX-induced cardiotoxicity (DIC). Androgen-induced gene 1 (AIG1) is perceived as a key regulator of oxidative stress-mediated cell death. Nonetheless, it remains elusive whether AIG1 is involved in the progression of DOX-induced cardiomyocyte ferroptosis and cardiotoxicity. Methods: C57BL/6 male mice were repeatedly administrated with DOX at an accumulative dosage of 20 mg/kg to establish a chronic DIC model. Global AIG1 knockout mice and AAV9-mediated cardiac-specific AIG1 knockdown or overexpression mice were utilized to evaluate the precise role of AIG1 in DIC. Additionally, the effects of AIG1 on cardiomyocyte ferroptosis were further investigated following DOX stimulation. Results: Ferroptosis played a pivotal role in DIC in both in vivo and in vitro settings. DOX exposure significantly reduced AIG1 expression levels in cardiomyocytes. Global AIG1 knockout or cardiac-specific AIG1 knockdown mice exhibited deteriorated cardiac function, adverse cardiac remodeling following DOX insult. Moreover, AIG1 deficiency aggravated DOX-evoked ferroptosis and oxidative stress in cardiomyocytes, whereas cardiac-specific overexpression of AIG1 conferred the protective effects manifested by the inhibition of cardiomyocyte ferroptosis and improvements in cardiac performance and remodeling under DOX challenge. Mechanistically, AIG1 directly interacted with the Pirh2 E3 ubiquitin ligase to promote the ubiquitination of p53, a key protein governing ferroptosis during DIC, thereby accelerating its degradation. Cardiac-specific Pirh2 knockdown markedly exacerbated DOX-induced ferroptosis by enhancing p53 activity in cardiomyocytes. Furthermore, the pharmacological administration of a highly selective p53 inhibitor PFT-α effectively ameliorated DIC in mice by inhibiting cardiomyocyte ferroptosis and substantially abrogated the deleterious cardiac effects associated with AIG knockout under DOX challenge. Conclusion: Our findings defined the critical cardioprotective role of AIG1 in DIC by alleviating cardiomyocyte ferroptosis in a Pirh2/p53 axis-dependent manner. Targeting the novelly identified AIG1-Pirh2-p53 signaling axis presents a promising approach to prevent DIC.
Targeted spleen modulation: a novel strategy for next-generation disease immunotherapy
Authors: Wei Dong, Yucheng Li, Qiaoman Fei, Senyang Li, Xinrui He, Yichao Chai, Junyi Zhou, Yujin Zong, Jing Geng, Zongfang Li
Journal: Theranostics (2025)

The spleen, the largest lymphatic organ, comprises a diverse array of immunocytes in approximately one quarter of the body, including T cells, B cells, natural killer cells, and myeloid cells (such as dendritic cells, neutrophils, myeloid-derived suppressor cells, and macrophages). These immune cells undergo dynamic transitions and mobilization, enabling the spleen to execute a wide range of immunological functions. The spleen's structural organization and multicellular composition, along with its reservoir of lymphocytes, facilitate the capture and clearance of blood-borne antigens while also orchestrating both innate and adaptive immune responses. Additionally, the spleen plays critical roles in hematopoiesis and the removal of aged or damaged red blood cells. Despite being innervated by sympathetic (catecholaminergic) nerve fibers, the spleen lacks parasympathetic (vagal or cholinergic) innervation. The neuroimmune axis, particularly the interplay between sympathetic and parasympathetic nervous system immune circuits, significantly influences disease onset and progression. Extensive research employing physical, genetic, and pharmacological approaches has sought to directly modulate splenic immunocytes and activate neuroimmune interactions to restore immune homeostasis and counteract disease. Two primary mechanisms underlie these immunomodulatory interventions: (1) the cholinergic anti-inflammatory pathway, wherein norepinephrine released by splenic catecholaminergic fibers binds to β2-adrenergic receptors on CD4⁺ T cells, triggering acetylcholine secretion, which in turn suppresses inflammatory cytokine production in macrophages via α7 nicotinic acetylcholine receptor signaling, and (2) direct immunomodulation of splenic immunocytes, which regulates key genes and signaling pathways, alters cytokine secretion, and modulates ion flux to influence cellular functions. Among various therapeutic strategies, physical methods, particularly electrical stimulation and splenic ultrasound stimulation, have demonstrated the greatest promise for clinical applications in splenic immunomodulation and disease management.