Journal of Clinical Investigation最新文献

{"title":"Retraction of Sorting protein VPS33B regulates exosomal autocrine signaling to mediate hematopoiesis and leukemogenesis.","authors":"Hao Gu, Chiqi Chen, Xiaoxin Hao, Conghui Wang, Xiaocui Zhang, Zhen Li, Hongfang Shao, Hongxiang Zeng, Zhuo Yu, Li Xie, Fangzhen Xia, Feifei Zhang, Xiaoye Liu, Yaping Zhang, Haishan Jiang, Jun Zhu, Jiangbo Wan, Chun Wang, Wei Weng, Jingjing Xie, Minfang Tao, Cheng Cheng Zhang, Junling Liu, Guo-Qiang Chen, Junke Zheng","doi":"10.1172/JCI197214","DOIUrl":"10.1172/JCI197214","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 16","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12352881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Using plasma cell-free mRNA to profile immune response and myocardial damage in immune checkpoint inhibitor-induced myocarditis.","authors":"Alireza Raissadati, Xuanyu Zhou, Harrison Chou, Yuhsin Vivian Huang, Shaheen Khatua, Yin Sun, Anne Xu, Sharon Loa, Arturo Hernandez, Han Zhu, Sean M Wu","doi":"10.1172/JCI188817","DOIUrl":"10.1172/JCI188817","url":null,"abstract":"<p><p>Plasma cell-free mRNA provides tissue-specific transcriptional profiling, precisely capturing cardiac damage and immune responses in immunotherapy-induced myocarditis.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 16","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12352903/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A noncanonical parasubthalamic nucleus-to-extended amygdala circuit converts chronic social stress into anxiety.","authors":"Na Liu, Jun Wang, Huan Wang, Bin Gao, Zheng Lin, Tian-Le Xu, Shumin Duan, Han Xu","doi":"10.1172/JCI188246","DOIUrl":"10.1172/JCI188246","url":null,"abstract":"<p><p>Anxiety disorders pose a substantial threat to global mental health, with chronic stress identified as a major etiologic factor. Over the past few decades, extensive studies have revealed that chronic stress induces anxiety states through a distributed neuronal network of interconnected brain structures. However, the precise circuit mechanisms underlying the transition from chronic stress to anxiety remain incompletely understood. Employing the chronic social defeat stress (CSDS) paradigm in mice, we uncovered a critical role of the parasubthalamic nucleus (PSTh) in both the induction and expression of anxiety-like behavior. The anxiogenic effect was mediated by an excitatory trisynaptic circuitry involving the lateral parabrachial nucleus (LPB), PSTh, and bed nucleus of the stria terminalis (BNST). Furthermore, CSDS downregulated Kv4.3 channels in glutamatergic neurons of the PSTh. Reexpression of these channels dampened neuronal overexcitability and alleviated anxiety-like behavior in stressed animals. In parallel with the well-known anxiety network centered on the amygdala, here we identify a noncanonical LPB-PSTh-BNST pathway in the transformation of stress into anxiety. These findings suggest that the PSTh may serve as a potential therapeutic target for anxiety-related disorders.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 16","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12352892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic risk in telomere biology disorders: it adds up.","authors":"Tanner O Monroe","doi":"10.1172/JCI195921","DOIUrl":"10.1172/JCI195921","url":null,"abstract":"<p><p>For many conditions, genotyping aids in clinical decision making. However, interpreting the clinical significance of genetic variants remains challenging, in part because a single risk variant does not always lead to disease, and variant carriers experience variable outcomes. One hypothesis underlying these phenomena, which are known as incomplete penetrance and variable expressivity, respectively, is that additional common genetic variation beyond the primary variant influences the presence and severity of disease. In this issue of JCI, Poeschla et al. present a compelling argument that common variants linked to telomere length act together with high-risk telomere biology disorder variants to scale outcomes. These data support a model in which many variants interact to shape cumulative risk.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 16","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12352884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SEC61B regulates calcium flux and platelet hyperreactivity in diabetes.","authors":"Yvonne X Kong, Rajan Rehan, Cesar L Moreno, Søren Madsen, Yunwei Zhang, Huiwen Zhao, Miao Qi, Callum B Houlahan, Siân P Cartland, Declan Robertshaw, Vincent Trang, Frederick Jun Liang Ong, Michael Liu, Edward Cheng, Imala Alwis, Alexander Dupuy, Michelle Cielesh, Kristen C Cooke, Meg Potter, Jacqueline Stöckli, Grant Morahan, Maggie L Kalev-Zylinska, Matthew T Rondina, Sol Schulman, Jean Y H Yang, G Gregory Neely, Simone M Schoenwaelder, Shaun P Jackson, David E James, Mary M Kavurma, Samantha L Hocking, Stephen M Twigg, James C Weaver, Mark Larance, Freda H Passam","doi":"10.1172/JCI184597","DOIUrl":"10.1172/JCI184597","url":null,"abstract":"<p><p>Platelet hyperreactivity increases the risk of cardiovascular thrombosis in diabetes and failure of antiplatelet drug therapies. Elevated basal and agonist-induced calcium flux is a fundamental cause of platelet hyperreactivity in diabetes; however, the mechanisms responsible for this remain largely unknown. Using a high-sensitivity, unbiased proteomic platform, we consistently detected over 2,400 intracellular proteins and identified proteins that were differentially released by platelets in type 2 diabetes. We identified that SEC61 translocon subunit β (SEC61B) was increased in platelets from humans and mice with hyperglycemia and in megakaryocytes from mice with hyperglycemia. SEC61 is known to act as an endoplasmic reticulum (ER) calcium leak channel in nucleated cells. Using HEK293 cells, we showed that SEC61B overexpression increased calcium flux into the cytosol and decreased protein synthesis. Concordantly, platelets in hyperglycemic mice mobilized more calcium and had decreased protein synthesis. Platelets in both humans and mice with hyperglycemia had increased ER stress. ER stress induced the expression of platelet SEC61B and increased cytosolic calcium. Inhibition of SEC61 with anisomycin decreased platelet calcium flux and inhibited platelet aggregation in vitro and in vivo. These studies demonstrate the existence of a mechanism whereby ER stress-induced upregulation of platelet SEC61B leads to increased cytosolic calcium, potentially contributing to platelet hyperreactivity in diabetes.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 16","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12352904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A distinct mechanism of epigenetic reprogramming silences PAX2 and initiates endometrial carcinogenesis.","authors":"Subhransu S Sahoo, Susmita G Ramanand, Ileana C Cuevas, Yunpeng Gao, Sora Lee, Ahmed Abbas, Xunzhi Zhang, Ashwani Kumar, Prasad Koduru, Sambit Roy, Russell R Broaddus, Victoria L Bae-Jump, Andrew B Gladden, Jayanthi Lea, Elena Lucas, Chao Xing, Akio Kobayashi, Ram S Mani, Diego H Castrillon","doi":"10.1172/JCI190989","DOIUrl":"10.1172/JCI190989","url":null,"abstract":"<p><p>Functional inactivation of tumor suppressor genes drives cancer initiation, progression, and treatment responses. Most tumor suppressor genes are inactivated through 1 of 2 well-characterized mechanisms: DNA-level mutations, such as point mutations or deletions, and promoter DNA hypermethylation. Here, we report a distinct third mechanism of tumor suppressor inactivation based on alterations to the histone rather than DNA code. We demonstrated that PAX2 is an endometrial tumor suppressor recurrently inactivated by a distinct epigenetic reprogramming event in more than 80% of human endometrial cancers. Integrative transcriptomic, epigenomic, 3D genomic, and machine learning analyses showed that PAX2 transcriptional downregulation is associated with replacement of open/active chromatin features (H3K27ac/H3K4me3) with inaccessible/repressive chromatin features (H3K27me3) in a framework dictated by 3D genome organization. The spread of the repressive H3K27me3 signal resembled a pearl necklace, with its length modulated by cohesin loops, thereby preventing transcriptional dysregulation of neighboring genes. This mechanism, involving the loss of a promoter-proximal superenhancer, was shown to underlie transcriptional silencing of PAX2 in human endometrial cancers. Mouse and human preclinical models established PAX2 as a potent endometrial tumor suppressor. Functionally, PAX2 loss promoted endometrial carcinogenesis by rewiring the transcriptional landscape via global enhancer reprogramming. The discovery that most endometrial cancers originate from a recurring epigenetic alteration carries profound implications for their diagnosis and treatment.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 16","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12352900/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to RAS interaction with PI3K p110α is required for tumor-induced angiogenesis.","authors":"Miguel Manuel Murillo, Santiago Zelenay, Emma Nye, Esther Castellano, Francois Lassailly, Gordon Stamp, Julian Downward","doi":"10.1172/JCI197925","DOIUrl":"10.1172/JCI197925","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 16","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12352882/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic targeting of PGBD5-dependent DNA damage in SMARCB1-deficient sarcomas.","authors":"Yaniv Kazansky, Helen S Mueller, Daniel Cameron, Phillip Demarest, Nadia Zaffaroni, Noemi Arrighetti, Valentina Zuco, Prabhjot S Mundi, Yasumichi Kuwahara, Romel Somwar, Rui Qu, Andrea Califano, Elisa de Stanchina, Filemon S Dela Cruz, Andrew L Kung, Mrinal M Gounder, Alex Kentsis","doi":"10.1172/JCI179282","DOIUrl":"10.1172/JCI179282","url":null,"abstract":"<p><p>Despite the potential of targeted epigenetic therapies, most cancers do not respond to current epigenetic drugs. The Polycomb repressive complex EZH2 inhibitor tazemetostat was recently approved for the treatment of SMARCB1-deficient epithelioid sarcomas, based on the functional antagonism between PRC2 and SMARCB1. Through the analysis of tazemetostat-treated patient tumors, we recently defined key principles of their response and resistance to EZH2 epigenetic therapy. Here, using transcriptomic inference from SMARCB1-deficient tumor cells, we nominated the DNA damage repair kinase ATR as a target for rational EZH2 combination epigenetic therapy. We showed that EZH2 inhibition promotes DNA damage in epithelioid and rhabdoid tumor cells, at least in part via its induction of piggyBac transposable element derived 5 (PGBD5). We leveraged this collateral synthetic lethal dependency to target PGBD5-dependent DNA damage by inhibition of ATR, but not CHK1, using the ATR inhibitor elimusertib. Consequently, combined EZH2 and ATR inhibition improved therapeutic responses in diverse patient-derived epithelioid and rhabdoid tumors in vivo. This advances a combination epigenetic therapy based on EZH2-PGBD5 synthetic lethal dependency suitable for immediate translation to clinical trials for patients.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144835252","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":"The NaV1.5 auxiliary subunit FGF13 modulates channels by regulating membrane cholesterol independent of channel binding.","authors":"Aravind R Gade, Mattia Malvezzi, Lala Tanmoy Das, Maiko Matsui, Cheng-I J Ma, Keon Mazdisnian, Steven O Marx, Frederick R Maxfield, Geoffrey S Pitt","doi":"10.1172/JCI191773","DOIUrl":"10.1172/JCI191773","url":null,"abstract":"<p><p>Fibroblast growth factor homologous factors (FHFs) bind to the cytoplasmic carboxy terminus of voltage-gated sodium channels (VGSCs) and modulate channel function. Variants in FHFs or VGSCs perturbing that bimolecular interaction are associated with arrhythmias. Like some channel auxiliary subunits, FHFs exert additional cellular regulatory roles, but whether these alternative roles affect VGSC regulation is unknown. Using a separation-of-function strategy, we show that a structurally guided, binding incompetent mutant FGF13 (the major FHF in mouse heart) confers complete regulation of VGSC steady-state inactivation (SSI), the canonical effect of FHFs. In cardiomyocytes isolated from Fgf13 knockout mice, expression of the mutant FGF13 completely restores wild-type regulation of SSI. FGF13 regulation of SSI derives from effects on local accessible membrane cholesterol, which is unexpectedly polarized and concentrated in cardiomyocytes at the intercalated disc (ID) where most VGSCs localize. Fgf13 knockout eliminates the polarized cholesterol distribution and causes loss of VGSCs from the ID. Moreover, we show that the previously described FGF13-dependent stabilization of VGSC currents at elevated temperatures depends on the cholesterol mechanism. These results provide new insights into how FHFs affect VGSCs and alter the canonical model by which channel auxiliary subunits exert influence.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144835253","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":"Elevated NR2F1 underlies the persistence of invasive disease after treatment of BRAF-mutant melanoma.","authors":"Manoela Tiago, Timothy J Purwin, Casey D Stefanski, Renaira Oliveira da Silva, Mitchell E Fane, Yash Chhabra, Jelan I Haj, Jessica Lf Teh, Rama Kadamb, Weijia Cai, Sheera R Rosenbaum, Vivian Chua, Nir Hacohen, Michael A Davies, Jessie Villanueva, Inna Chervoneva, Ashani T Weeraratna, Dan A Erkes, Claudia Capparelli, Julio A Aguirre-Ghiso, Andrew E Aplin","doi":"10.1172/JCI178446","DOIUrl":"10.1172/JCI178446","url":null,"abstract":"<p><p>Despite the success of targeted inhibitors in cutaneous melanoma, therapeutic responses are limited by the aged tumor microenvironment and drug-tolerant residual cells. Given the similarities between drug tolerance and cellular dormancy, we studied the dormancy marker, nuclear receptor subfamily 2 group F member 1 (NR2F1), in response to BRAF-V600E inhibitors (BRAFi) plus MEK inhibitors (MEKi) in BRAF-mutant melanoma models. Transcriptomic analysis of melanoma patient samples treated with BRAFi + MEKi showed increased NR2F1. NR2F1 was highly expressed in the drug-tolerant invasive cell state of minimal residual disease in patient-derived and mouse-derived xenografts on BRAFi + MEKi. NR2F1 over-expression was sufficient to reduce BRAFi + MEKi effects on tumor growth in vivo, and cell proliferation, death, and invasion in vitro. Effects were linked to genes involved in mTORC1 signaling. These cells were sensitive to the combination of BRAFi, MEKi plus rapamycin. Melanomas from aged mice, known to exhibit decreased responses to BRAFi + MEKi, displayed higher levels of NR2F1 compared to tumors from young mice. Depleting NR2F1 in an aged mouse melanomas improved the response to targeted therapy. These findings show high NR2F1 expression in 'invasive-state' residual cells and that targeting NR2F1-high cells with mTORC1 inhibitors may improve outcomes in patients with melanoma.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 18","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}