Cell Reports MedicinePub Date : 2026-10-20Epub Date: 2026-09-30DOI: 10.1016/j.xcrm.2026.103083
Beatriz German, Katherine L Morel, Teia Noel, Nadia Boufaied, Deborah L Burkhart, Sujun Chen, Felipe Dezem, Xintao Qiu, Henry W Long, Kun-Lin Ho, Stefan DiFazio, Sylvan Baca, Ayesha A Shafi, Matthew L Freedman, Himisha Beltran, Christopher J Sweeney, Housheng Hansen He, Myles Brown, Jasmine T Plummer, Simon R V Knott, David P Labbé, Leigh Ellis
{"title":"EZH2-dependent phenotypic plasticity reveals TTP-associated and mTORC1 therapeutic vulnerabilities in lethal prostate cancer.","authors":"Beatriz German, Katherine L Morel, Teia Noel, Nadia Boufaied, Deborah L Burkhart, Sujun Chen, Felipe Dezem, Xintao Qiu, Henry W Long, Kun-Lin Ho, Stefan DiFazio, Sylvan Baca, Ayesha A Shafi, Matthew L Freedman, Himisha Beltran, Christopher J Sweeney, Housheng Hansen He, Myles Brown, Jasmine T Plummer, Simon R V Knott, David P Labbé, Leigh Ellis","doi":"10.1016/j.xcrm.2026.103083","DOIUrl":"10.1016/j.xcrm.2026.103083","url":null,"abstract":"<p><p>Phenotypic plasticity is a recognized mechanism of therapeutic resistance in prostate cancer (PCa); however, current knowledge of its underlying drivers and therapeutic interventions remain limited. Using genetically engineered mouse models (GEMMs) devoid of Pten and Rb1, we previously demonstrated the chromatin reprogramming factor enhancer of zeste homolog 2 (EZH2) as a regulator of alternative transcription programs promoting phenotypic plasticity. Here, using a multi-omics approach, we demonstrate that EZH2 regulates multilineage cell states and identify the RNA-binding protein Tristetraprolin (TTP) as a contributor to the response to EZH2 therapy through its role in RNA stability and translational regulation. Combined pharmacological inhibition of EZH2 and PI3K/mTORC1 produces superior antitumor activity in murine and human models of phenotypic plasticity, with greatest efficacy observed when combined with castration. Together, these findings identify EZH2-PI3K/mTORC1 signaling as a therapeutic vulnerability in phenotypically plastic PCa and reveal TTP-associated regulatory programs as contributors to targeted therapy response.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103083"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2026-10-20Epub Date: 2025-10-14DOI: 10.1016/j.xcrm.2025.102418
James R Lindsay, Jennifer Altreuter, Joao V Alessi, Jason L Weirather, Anita Giobbie-Hurder, Ian Dryg, Katharina Hoebel, Bijaya Sharma, Kristen Felt, F Stephen Hodi, Neal Lindeman, Lynette M Sholl, Ethan Cerami, Jonathan A Nowak, Mark M Awad, Scott J Rodig, William Lotter
{"title":"Pan-cancer spatial characterization of key immune biomarkers in the tumor microenvironment.","authors":"James R Lindsay, Jennifer Altreuter, Joao V Alessi, Jason L Weirather, Anita Giobbie-Hurder, Ian Dryg, Katharina Hoebel, Bijaya Sharma, Kristen Felt, F Stephen Hodi, Neal Lindeman, Lynette M Sholl, Ethan Cerami, Jonathan A Nowak, Mark M Awad, Scott J Rodig, William Lotter","doi":"10.1016/j.xcrm.2025.102418","DOIUrl":"10.1016/j.xcrm.2025.102418","url":null,"abstract":"<p><p>Deciphering the composition and spatial organization of the tumor immune microenvironment (TIME) is key to understanding cancer progression and treatment response. Spatial biology techniques such as multiplex immunofluorescence (mIF) offer detailed insights but are often limited to retrospective studies of individual cancer types. Here, we provide a pan-cancer spatial characterization of key biomarkers (CD8, FOXP3, PD-1, and PD-L1) using an mIF assay performed prospectively in a clinical setting on 2,019 tumors across 14 major cancer types. By integrating interpretable compositional and spatial metrics, we identify patterns of TIME variation conserved across cancer types and stages. We assess associations between these TIME spatial factors and tumor, genomic, and clinical features, with results extending prior findings and uncovering new links. To accompany the analysis, we provide a curated database of the 39.4 million spatially resolved cells. Altogether, our findings and database offer pan-cancer insights of the TIME to advance spatial biology and cancer immunology.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102418"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145298985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2026-10-20Epub Date: 2026-08-05DOI: 10.1016/j.xcrm.2026.102962
Byron W H Mui, Evgenios Neofytou, Joseph C Wu
{"title":"Clinical landscape of human pluripotent stem cell-derived cardiomyocyte therapy.","authors":"Byron W H Mui, Evgenios Neofytou, Joseph C Wu","doi":"10.1016/j.xcrm.2026.102962","DOIUrl":"10.1016/j.xcrm.2026.102962","url":null,"abstract":"<p><p>Heart failure is a major clinical and economic burden that afflicts 60 million individuals worldwide. Guideline-directed medical therapies can slow disease progression, but they cannot restore the loss of cardiomyocytes. Over the past two decades, human pluripotent stem cell (hPSC)-based technology has emerged as a leading approach to overcome limited cardiac regenerative capacity, offering a scalable source of functional human cardiomyocytes. The field is now at a pivotal translational stage, as advances in differentiation and tissue engineering have enabled hPSC-based products to enter first-in-human clinical trials. In this review, we summarize the pathophysiological rationale for cell-based therapy in heart failure with reduced ejection fraction. Then, we examine the preclinical foundations of distinct hPSC-derived product formats, including cell suspensions, epicardial sheets, engineered heart muscle, and cardiac spheroids, each with distinct tradeoffs and translational considerations. We conclude by providing updates on ongoing and recently completed clinical trials, evaluating their safety, feasibility, and preliminary efficacy outcomes.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102962"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148676876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2026-10-20Epub Date: 2026-09-24DOI: 10.1016/j.xcrm.2026.103076
Biana Bernshtein, Julia A Zhiteneva, Jeshina Janardhanan, Chanchal Wagh, Meagan Kelly, Smriti Verma, Christina S Faherty, Angel Nikolov, Wonyeong Jung, Salima Raiyan Basher, Mohammad Ashraful Amin, Shakil Mahamud, Nazmul Hasan Rajib, Fahima Chowdhury, Ashraful Islam Khan, Richelle C Charles, Peng Xu, Pavol Kováč, Subhra Chakraborty, Robert W Kaminski, Galit Alter, Taufiqur R Bhuiyan, Firdausi Qadri, Edward T Ryan
{"title":"Functional O-specific polysaccharide-specific antibody responses in young children following Shigella infection in Bangladesh.","authors":"Biana Bernshtein, Julia A Zhiteneva, Jeshina Janardhanan, Chanchal Wagh, Meagan Kelly, Smriti Verma, Christina S Faherty, Angel Nikolov, Wonyeong Jung, Salima Raiyan Basher, Mohammad Ashraful Amin, Shakil Mahamud, Nazmul Hasan Rajib, Fahima Chowdhury, Ashraful Islam Khan, Richelle C Charles, Peng Xu, Pavol Kováč, Subhra Chakraborty, Robert W Kaminski, Galit Alter, Taufiqur R Bhuiyan, Firdausi Qadri, Edward T Ryan","doi":"10.1016/j.xcrm.2026.103076","DOIUrl":"10.1016/j.xcrm.2026.103076","url":null,"abstract":"<p><p>Shigellosis is the second leading cause of diarrheal death in children under 5 years globally, yet no licensed vaccine exists, partly due to poor understanding of protective immunity in young children, especially in endemic settings. Here, we applied a functional antibody-profiling approach to define Shigella-specific antibody responses in young children versus older individuals with culture-confirmed shigellosis in Bangladesh. We found that higher baseline O-specific polysaccharide (OSP)-specific and protein-specific IgG and FcγR binding levels correlated with less severe disease regardless of age. We also found that over time, individuals under 5 years of age developed a less functional and durable response against OSP than older individuals. We demonstrate that OSP-specific IgG increased uptake of live Shigella by monocytes and macrophages in an Fc-dependent mechanism. Our findings suggest that young children develop limited OSP-specific functional antibody responses that fail to maximally involve innate immune cells. Innate cell clearance may be important in protecting against Shigella.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103076"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Structural basis for broad orthopoxvirus neutralization by two antibodies targeting distinct L1R epitopes.","authors":"Li Chen, Guanying Zhang, Haotian Lin, Yue Zhang, Jingfei Li, Linfeng Shu, Xiaolin Wang, Ruihua Li, Fangxin Zhao, Xiaofan Zhao, Yilong Yang, Zhang Zhang, Jun Zhang, Congwen Wei, Xiangyang Chi, Xiaodong Zai, Junjie Xu","doi":"10.1016/j.xcrm.2026.103077","DOIUrl":"10.1016/j.xcrm.2026.103077","url":null,"abstract":"<p><p>The 2022 mpox outbreak highlights the persistent threat posed by the mpox virus (MPXV) and related orthopoxviruses (OPXVs). Yet, approved antibody-based therapeutics for OPXVs are lacking. Here, we present two broadly neutralizing monoclonal antibodies (mAbs), G4 and B9, that target the MPXV M1R protein, homologous to L1R in other OPXVs. Both mAbs demonstrate cross-reactive binding and robust neutralization against multiple pathogenic OPXVs. Notably, G4 exhibits exceptional potency, neutralizing mature virions of VACV with an IC<sub>50</sub> of 37.93 pM, whereas B9 has an IC<sub>50</sub> of 41.13 nM. Cryo-electron microscopy analysis reveals that G4 and B9 target distinct epitopes on M1R. G4 recognizes a conventional conformational epitope but overcomes neutralization escape associated with the Asp35 residue, whereas B9 binds to an epitope on the lateral β-sheets of M1R. Our findings provide two promising candidates with complementary neutralization profiles for the development of broad-spectrum prophylactic and therapeutic interventions against OPXV infections.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103077"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2026-10-20Epub Date: 2026-09-10DOI: 10.1016/j.xcrm.2026.103027
Rajesh Kumar, Parth Desai, Rajaa El Meskini, Chirayu Mohindroo, Alexandra Ágnes Benő, Devon Atkinson, Michael Nirula, Laura Bassel, Nobuyuki Takahashi, Kelly L Sovacool, Anna Meinhardt, Mohit Arora, Kanak Parmar, Darryl Nausome, Samantha Nichols, Linda Sciuto, Shannon Swift, Kolos Nemes, Ajit Kumar Sharma, Nathan Pate, Arun Rajan, Elliot Levy, Michael Kassin, Christopher Febres Aldana, Vishal Koparde, Melissa Galloux, Roshan Shreshta, Zoe Weaver Ohler, Lorinc Pongor, Anish Thomas
{"title":"A stem-like chromatin program in small-cell lung cancer is associated with poor outcomes after chemoimmunotherapy.","authors":"Rajesh Kumar, Parth Desai, Rajaa El Meskini, Chirayu Mohindroo, Alexandra Ágnes Benő, Devon Atkinson, Michael Nirula, Laura Bassel, Nobuyuki Takahashi, Kelly L Sovacool, Anna Meinhardt, Mohit Arora, Kanak Parmar, Darryl Nausome, Samantha Nichols, Linda Sciuto, Shannon Swift, Kolos Nemes, Ajit Kumar Sharma, Nathan Pate, Arun Rajan, Elliot Levy, Michael Kassin, Christopher Febres Aldana, Vishal Koparde, Melissa Galloux, Roshan Shreshta, Zoe Weaver Ohler, Lorinc Pongor, Anish Thomas","doi":"10.1016/j.xcrm.2026.103027","DOIUrl":"10.1016/j.xcrm.2026.103027","url":null,"abstract":"<p><p>Small-cell lung cancer (SCLC) is an aggressive malignancy with substantial tumor heterogeneity and limited clinically actionable biomarkers beyond established features such as liver metastases. We profile tumor-intrinsic chromatin accessibility in a patient-derived xenograft biobank and identify three recurrent chromatin programs: neuroendocrine, marked by ASCL1/NEUROD1 activity; immunogenic, marked by IRF-associated activity; and stem-like, marked by TEAD/OCT activity. These programs are reproduced at the cohort level across bulk and single-cell transcriptomic datasets comprising more than 800 tumors, including 300 extensive-stage samples. In patients treated with chemoimmunotherapy, the stem-like program is associated with inferior survival, including a median overall survival of 7.41 months versus 15.9 and 12.6 months for immunogenic and neuroendocrine groups, respectively. This association remains significant after adjustment for liver metastases, brain metastases, and elevated lactate dehydrogenase. These findings support a high-risk stem-like SCLC chromatin program for prospective biomarker refinement and therapeutic investigation.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103027"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148929164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2026-10-20Epub Date: 2026-09-24DOI: 10.1016/j.xcrm.2026.103075
Tongyu Chen, Zetian Jia, Ying Tang, Jianjian Zhang, Yi Zhang, Xiaojian Li, Jiazhi Jiang, Jin Yu, Tingbao Zhang, Dongliang Guo, Da Liu, Hao Peng, Jincao Chen, Wei Wei, Wei Li, Yibin Liu, Xiang Li
{"title":"Genome-wide cell-free DNA methylation profiling via TAPS for moyamoya disease diagnosis and postoperative collateral formation prediction.","authors":"Tongyu Chen, Zetian Jia, Ying Tang, Jianjian Zhang, Yi Zhang, Xiaojian Li, Jiazhi Jiang, Jin Yu, Tingbao Zhang, Dongliang Guo, Da Liu, Hao Peng, Jincao Chen, Wei Wei, Wei Li, Yibin Liu, Xiang Li","doi":"10.1016/j.xcrm.2026.103075","DOIUrl":"10.1016/j.xcrm.2026.103075","url":null,"abstract":"<p><p>Moyamoya disease (MMD) lacks reliable biomarkers for distinguishing it from atherosclerotic cerebrovascular disease (ACVD) and predicting postoperative collateral formation (PCF). Here, we apply low-input, bisulfite-free TET-assisted pyridine borane sequencing to plasma cell-free DNA (cfDNA) from 39 MMD and 37 ACVD patients in the discovery cohort and 40 MMD and 16 ACVD patients in an external multicenter cohort. The same libraries enable the analysis of methylation, fragmentation, end-nucleotide composition, nucleosome positioning, and tissue-of-origin signals. Although global methylation and tissue-of-origin profiles are broadly similar, differentially methylated regions distinguish MMD from ACVD and associate with PCF. A cfDNA methylation model achieves areas under the curve (AUCs) of 0.923 and 0.822 in the discovery and external cohorts, respectively, while a separate model predicts PCF with AUCs of 0.907 and 0.854. These findings provide proof-of-concept evidence for cfDNA methylation profiling as a minimally invasive approach to MMD diagnosis and preoperative assessment, while establishing an epigenomic resource for future studies.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103075"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2026-10-20Epub Date: 2026-10-07DOI: 10.1016/j.xcrm.2026.103095
Xin Wang, Yusha Sun, Prithvi Sinha, Ruiying Su, Daniel Y Zhang, Kristen H Park, Yao Fu, Weifan Dong, Zhijian Zhang, Qing Wang, Daniel H Geschwind, Riki Kawaguchi, Emily Ling-Lin Pai, Maria A Gubbiotti, Robert Colbourn, Nduka M Amankulor, Jay F Dorsey, MacLean P Nasrallah, Stephen J Bagley, Zev A Binder, Donald M O'Rourke, Yi Fan, Guo-Li Ming, Hongjun Song
{"title":"A standardized patient-derived glioblastoma organoid platform for evaluating radiotherapy efficacy and overcoming resistance.","authors":"Xin Wang, Yusha Sun, Prithvi Sinha, Ruiying Su, Daniel Y Zhang, Kristen H Park, Yao Fu, Weifan Dong, Zhijian Zhang, Qing Wang, Daniel H Geschwind, Riki Kawaguchi, Emily Ling-Lin Pai, Maria A Gubbiotti, Robert Colbourn, Nduka M Amankulor, Jay F Dorsey, MacLean P Nasrallah, Stephen J Bagley, Zev A Binder, Donald M O'Rourke, Yi Fan, Guo-Li Ming, Hongjun Song","doi":"10.1016/j.xcrm.2026.103095","DOIUrl":"10.1016/j.xcrm.2026.103095","url":null,"abstract":"<p><p>Patient-derived glioblastoma (GBM) organoids (GBOs) maintain characteristics of their original tumors; however, they have not been widely applied to systematically assess therapy responses at scale or elucidate mechanisms underlying treatment resistance. Here, we develop a standardized reaggregated GBO (rGBO) platform for scalable, quantitative evaluation of radiation responses across 48 patients with GBM. Radiation responses in rGBOs correlate with the survival duration of corresponding patients treated with standard-of-care radiotherapy. Transcriptomic analyses identify gene signatures associated with radiosensitivity and radioresistance. Connectivity mapping with perturbational datasets identifies a panel of compounds with potential for reducing radioresistant and enhancing radiosensitive signatures. Subsequent testing demonstrates that inhibitors of bromodomain and extraterminal (BET) family proteins enhance radiotherapy efficacy in GBO and xenograft models by downregulating the radioresistant signature. Together, our study highlights the potential of rGBOs for standardizing therapeutic screening, evaluating patient-specific responses, identifying associated molecular features, and developing strategies to overcome treatment resistance.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103095"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2026-10-20Epub Date: 2026-10-08DOI: 10.1016/j.xcrm.2026.103106
Jérôme Delplanque, Audrey Leloire, Lauriane Le Collen, Hélène Loiselle, Bénédicte Toussaint, Emmanuel Vaillant, Frédéric Allegaert, Timothée Beke, Guillaume Charpentier, Sylvia Franc, Beverley Balkau, Michel Marre, Emma Henriques, Emmanuel Buse Falay, Mehdi Derhourhi, Philippe Froguel, Amélie Bonnefond
{"title":"Human genetic evidence challenges NCOA1 as a monogenic obesity gene.","authors":"Jérôme Delplanque, Audrey Leloire, Lauriane Le Collen, Hélène Loiselle, Bénédicte Toussaint, Emmanuel Vaillant, Frédéric Allegaert, Timothée Beke, Guillaume Charpentier, Sylvia Franc, Beverley Balkau, Michel Marre, Emma Henriques, Emmanuel Buse Falay, Mehdi Derhourhi, Philippe Froguel, Amélie Bonnefond","doi":"10.1016/j.xcrm.2026.103106","DOIUrl":"10.1016/j.xcrm.2026.103106","url":null,"abstract":"<p><p>Obesity is a heterogeneous disease with a substantial genetic component. Rare pathogenic variants in genes of the leptin-melanocortin pathway can cause monogenic obesity and support targeted therapies such as setmelanotide, a melanocortin 4 receptor agonist. Pathogenic variants in NCOA1, encoding the nuclear receptor co-activator SRC-1, have recently been proposed as a cause of monogenic obesity through impaired leptin-induced POMC activation, leading to the inclusion of NCOA1 variant carriers in the EMANATE setmelanotide trial. However, despite biological rationale, the contribution of NCOA1 variants to human obesity remains elusive. Here, we assess NCOA1 variants with case-control analyses in adults and children from the RaDiO study, combined with in vitro assays and replication in the UK Biobank. We find no association between pathogenic NCOA1 variants and obesity or body mass index.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103106"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jacqueline A Koehler, Laurie L Baggio, Xiemin Cao, Rui Shang, Bernardo Yusta, Chi Kin Wong, Dianne Matthews, Darleen A Sandoval, Daniel J Drucker
{"title":"Gut-derived glucagon-like peptides attenuate T cell-induced intestinal injury.","authors":"Jacqueline A Koehler, Laurie L Baggio, Xiemin Cao, Rui Shang, Bernardo Yusta, Chi Kin Wong, Dianne Matthews, Darleen A Sandoval, Daniel J Drucker","doi":"10.1016/j.xcrm.2026.103115","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103115","url":null,"abstract":"<p><p>Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are produced in enteroendocrine L cells and control energy homeostasis. GLP-1 receptor (GLP-1R) activation improves glucose homeostasis and induces satiety and weight loss, whereas GLP-2 receptor (GLP-2R) signaling promotes intestinal growth and nutrient absorption. GLP-1R and GLP-2R agonism also reduce intestinal damage in preclinical studies. Here, we demonstrate that endogenous GLP-1R and GLP-2R signaling are essential for protecting the intestine from T cell-mediated enteropathy. Gut injury induced by T cell activation is increased in Glp1r<sup>-/-</sup> and Glp2r<sup>-/-</sup> mice, as well as in mice with selective loss of intestinal proglucagon gene expression (Gcg<sup>Gut-/-</sup>). Conversely, the GLP-2R agonist teduglutide and the GLP-1R agonist semaglutide, administered separately or together, attenuate αCD3-induced intestinal damage in Gcg<sup>Gut-/-</sup> mice. Collectively, these findings demonstrate distinct biological roles for endogenous GLP-1R/GLP-2R activity in immune-mediated intestinal injury and highlight the therapeutic potential of glucagon-like peptides, alone or together, for ameliorating T cell-mediated mucosal injury.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103115"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149227389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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