Journal of Clinical Investigation最新文献

{"title":"Cellular senescence mediates facioscapulohumeral muscular dystrophy.","authors":"Usuk Jung, Erdong Wei, Ana Mitanoska, Philipp Heher, Kenric Chen, Haseeb Ahsan, Xu Zhang, Giorgio Tasca, Paul D Robbins, Nathan K LeBrasseur, Michael Kyba, Darko Bosnakovski","doi":"10.1172/JCI207716","DOIUrl":"https://doi.org/10.1172/JCI207716","url":null,"abstract":"<p><p>Facioscapulohumeral muscular dystrophy (FSHD) is driven by aberrant expression of the early embryonic transcription factor Double Homeobox 4 (DUX4), yet the mechanisms linking low, sporadic DUX4 activity to progressive muscle degeneration remain unclear. Here, we identify cellular senescence as a central and early mechanism in FSHD pathogenesis. Analysis of patient muscle transcriptomes revealed strong enrichment of senescence and senescence-associated secretory phenotype (SASP) programs that correlated with DUX4 activity, clinical severity, and histopathological changes. Notably, these signatures were detectable even in STIR-negative muscles, defining a prodystrophic state characterized by early molecular alterations preceding overt MRI-detectable inflammation and highlighting their potential utility as early biomarkers of disease activity. Using an FSHD mouse model, we show that DUX4-induced muscle injury rapidly triggers senescence, which then progressively expands. Fibroadipogenic progenitors and macrophages emerged as the principal senescent populations and key sources of pro-inflammatory and profibrotic SASP signals. Importantly, senescence was therapeutically modifiable. Treatment with the nucleoside reverse transcriptase inhibitor lamivudine (3TC), which inhibits LINE-1 reverse transcriptase activity, significantly reduced senescence, inflammation, and fibrosis while promoting muscle regeneration. These findings identify cellular senescence as a tractable driver of FSHD and warrant senotherapeutic strategies, particularly lamivudine, for clinical intervention in FSHD.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149342374","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":"Decidua-accumulated effector-like memory CD8+ T cells orchestrate localized antimicrobial defense without compromising fetal tolerance.","authors":"Lu Liu, Xixi Huang, Tingxuan Yin, Xianyang Hu, Hailin Yu, Guohua Zhu, Chunfang Xu, Jiajia Chen, Jiangyuan Du, Hongyan Wang, Qingyu Wu, Wei Zhang, Feng Wang, Huimei Wu, Meirong Du","doi":"10.1172/JCI202874","DOIUrl":"https://doi.org/10.1172/JCI202874","url":null,"abstract":"<p><p>Deciphering immune privilege at the maternal-fetal interface is essential for understanding how reproductive success and host defense are simultaneously maintained. Decidualization, occurring within the specialized stromal tissue encapsulating the fetus and placenta, shapes local immune adaptation required for healthy pregnancy. Here, we identify a decidua-enriched effector-like memory CD8+ T cell subset marked by CD45RA in humans and CX3CR1 in mice. These cells preferentially accumulate in the decidua, which harbors a CX3CL1-dominant chemokine niche, and disruption of Cx3cr1 or uterine Cx3cl1 impaired their decidual recruitment and tissue localization. Human CD45RA+ and murine CX3CR1+ decidual memory CD8+ T cells shared conserved transcriptional and functional features, including enhanced cytotoxic potential and limited inflammatory cytokine production. Functionally, CX3CL1-mediated CD8+ T cell accumulation improved local control of prenatal Listeria monocytogenes infection and reduced infection-associated fetal loss. In contrast, fetal antigen-specific CD8+ T cell accumulation and fetal resorption occurred independently of uterine CX3CL1. Together, our findings define the maternal-fetal interface as an active immunological gatekeeper, that compartmentalizing CD8+ T cell-mediated antimicrobial adaptive immunity through the conserved CX3CL1-CX3CR1 axis, supporting pathogen-specific defense while preserving fetal tolerance.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149342386","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":"Biological sex-dependent hormonal signaling and metabolomic profiles in obesity alter tumor microenvironment and immunotherapy outcomes.","authors":"Logan V Vick, Spencer R Rosario, Ziming Wang, Craig Collins, Lam T Khuat, Yatian Yang, Michael K Sheng, Wahed A Firoz, Ryan N Nielsen, Yao-Hui Sun, Aryana M Razmara, Hossein Borghaei, Emmanuel S Antonarakis, Andrew Elliott, Nishant Gandhi, Raid Aljumaily, Sami Ibrahimi, Michael Machiorlatti, Sara K Vesely, Shuchi Gulati, Sarbajit Mukherjee, Robert J Canter, Sean J Judge, Arta M Monjazeb, William J Murphy","doi":"10.1172/JCI203453","DOIUrl":"https://doi.org/10.1172/JCI203453","url":null,"abstract":"<p><p>Commonly viewed as a negative prognostic factor in cancer, obesity is associated with improved responses to cancer immunotherapy using immune checkpoint inhibitors (ICIs). Although data suggest a sexual dimorphism influencing the effects of obesity on immunotherapy responses, to our knowledge, the intersection of sex and obesity on immunotherapy requires further exploration. We demonstrate, in a pan-cancer analysis stratified by sex and BMI, that obesity (BMI ≥ 30) is associated with improved survival after ICI only in male patients. In preclinical models of diet-induced obesity (DIO), we observed that only DIO male tumor-bearing mice responded better to ICI. The differential effect of sex on outcomes was associated with alterations in the tumor microenvironment where DIO female mice demonstrated increased tumor-associated macrophages skewed toward a M2 phenotype. Ovariectomy of DIO female mice reduced M2 polarization and increased anti-tumor immune responses including increases in tumor-infiltrating T cells following ICI. Metabolomic analysis of DIO mice demonstrated distinct profiles base on sex. Re-stratification of female cancer patients revealed that obesity was associated with improved outcome, but only in post-menopausal (age ≥ 55) patients. We identify that the immunotherapy \"obesity paradox\" is sex-dependent and that hormonal and metabolomic status modulates the influence of obesity on ICIs.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149321694","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":"Synthetic immunological niche reveals early immune dysregulation and stratifies therapeutic response in type 1 diabetes.","authors":"Jyotirmoy Roy, Yifei Jiang, Runbo Mao, Jessica L King, Amod Talekar, Donglin Liu, Lillian Holman, Haoxuan Zeng, Xin Luo, Laila M Rad, Peter Sajjakulnukit, Brianna Ha, Kai Liu, Elizabeth J Bealer, Bryan Wonski, Kathryn Kang, Sean T Carey, Luke F Bugada, Brooke M Smiley, Shahzad Sohail, Antonio D Holmes, Dominik Awad, Aaron H Morris, Costas A Lyssiotis, Jie Liu, Lonnie D Shea","doi":"10.1172/JCI206433","DOIUrl":"https://doi.org/10.1172/JCI206433","url":null,"abstract":"<p><p>In Type 1 Diabetes (T1D), disease onset and immunotherapy responses vary widely, reflecting heterogeneous stage-specific immune dysregulation that remains undefined. To investigate this heterogeneity, we engineered microporous polycaprolactone scaffolds that form synthetic immunological niches (INs) subcutaneously and capture tissue-associated systemic immune changes. Building on our prior demonstration of IN-based longitudinal T1D monitoring, we use multimodal IN profiling to define the immune changes underlying divergent disease trajectories and immunotherapy responses. In non-obese diabetic (NOD) mice, longitudinal transcriptomic profiling of IN identified early myeloid associated changes, followed by increasing T cell-associated dysregulation that distinguished progressors from non-progressors. An early-stage IN-based T1D gene signature stratified NOD progressors from non-progressors by 6 weeks of age and was conserved across human T1D tissues, distinguishing T1D from non-diabetic individuals in spleen and pancreatic lymph node samples, but not in peripheral blood. Signature-based stratification revealed macrophage-associated TNFα pathway enrichment in pancreas of NOD progressors, which was validated in human T1D islets. Given the heterogeneous response to anti-TNFα therapy, IN profiling identified genesets associated with anti-TNFα efficacy and generated a response score that prospectively distinguished treatment-sensitive from resistant mice. These findings establish IN as a platform for detecting stage-wise immune dysregulation and stratifying immunotherapy response in T1D.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149321695","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":"Targeted gene therapy alleviates epilepsy and hyperexcitability in models of SCN2A deficiency.","authors":"Zaiyang Zhang, Jingliang Zhang, Xiaoling Chen, Brody A Deming, Shivam Kant, Purba Mandal, Harish Kothandaraman, Phillip J SanMiguel, Manasi S Halurkar, Akila D Abeyaratna, Morgan J Robinson, Iuliia Vitko, Ronald P Gaykema, Chongli Yuan, Nadia A Lanman, Matthew T Tegtmeyer, Dan Wang, Guangping Gao, Riyi Shi, Edward Perez-Reyes, Yang Yang","doi":"10.1172/JCI196068","DOIUrl":"https://doi.org/10.1172/JCI196068","url":null,"abstract":"<p><p>Pathogenic SCN2A loss-of-function (LoF) variants can cause severe, refractory epilepsy with limited treatment options. Existing Scn2a-LoF mouse models exhibit few spontaneous seizures, limiting the dynamic range needed to assess therapeutic efficacy. We therefore generated gene-trap Scn2a-deficient mice on the seizure-prone DBA/2J background. These mice experienced hundreds of spontaneous absence seizures per day, characterized by concurrent behavioral arrest and EEG spike-wave discharges (SWDs). Partial restoration of Scn2a expression reduced seizure burden. Electrophysiological analysis revealed impaired action potential waveforms yet increased repetitive firing, alongside coordinated downregulation of voltage-gated potassium channel genes, potentially contributing to hyperexcitability. Given the broad potassium channel downregulation and prior efficacy of KCNA1 gene therapy in refractory seizure models, we selected KV1.1 as a potential therapeutic target and used a drug-controllable adeno-associated virus (AAV) to express human KCNA1. We found that this intervention normalized elevated neuronal firing and reduced spontaneous seizure burden in Scn2a-deficient mice. Extending these findings to a human cell-based platform, AAV-mediated KCNA1 expression also reduced neuronal firing in human cortical organoids carrying a SCN2A-truncating variant identified in patients. Together, these findings provide proof of principle for drug-controllable KCNA1 gene therapy as a promising treatment avenue for epilepsy related to SCN2A LoF variants.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149321696","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":"Nuclear cGAS governs transcription to control lipid metabolism, tumor growth, and therapy response.","authors":"Yu Deng, Matthew J Niederhuber, Zhichuan Zhu, Austin J Hepperla, Le Yu, Quentin Hahn, Joshua Hartsell, Tooba Rashid, Piotr A Mieczkowski, Hemant Kelkar, Jeremy M Simon, Yanqiong Zhang, Alessandra Livraghi-Butrico, Meredith J Zeller, Joseph Gc Kennedy, Jazmin F DePriest, Jiong Li, Yan Zhang, Xing Qiu, H Ümit Kaniskan, Jian Jin, Corbin D Jones, Laura E Herring, Douglas H Phanstiel, Xiaojing Liu, Jesse R Raab, Brian D Strahl, Pengda Liu","doi":"10.1172/JCI205579","DOIUrl":"https://doi.org/10.1172/JCI205579","url":null,"abstract":"<p><p>Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor critical for host defense against microbial infections. To prevent aberrant activation, nuclear cGAS is restrained by nucleosome tethering or by barrier-to-autointegration factor-mediated restriction of its access to DNA. However, its physiological roles beyond enzymatic suppression in the nucleus remain poorly understood. Here, we present a genome-wide map of cGAS chromatin localization in human cells and unexpectedly find its binding beyond nucleosome tethering, where cGAS is recruited to chromatin by AP-1 transcription factors via a potentially previously uncharacterized transactivation domain. Integrated CUT&RUN, RNA-seq, and metabolomics analyses reveal that cGAS transcriptionally regulates cholesterol homeostasis. Mechanistically, cGAS promotes LGALS3 transcription, which inhibits ACAA2 activity to suppress fatty acid oxidation and acetyl-CoA production, thereby lowering intracellular cholesterol levels. Reduced cholesterol lowers plasma membrane phosphatidylinositol [3,4,5] triphosphate [PI(3,4,5)P3] levels and decreases mTOR complex 2 (mTORC2) activation. In contrast, cGAS depletion results in cholesterol accumulation and elevated PI(3,4,5)P3, driving mTORC2/Akt signaling, promoting xenografted tumor growth, and conferring resistance to DNA-damaging agents. In vivo, the elevated hepatic cholesterol levels observed in cGas-/- mice were largely reversed by inhibition of Akt but not STING, whereas cGAS deficiency had minimal effects on lung physiology. Collectively, our findings uncover an unexpected role for nuclear cGAS in orchestrating a transcriptional program that links lipid metabolism to cell proliferation, stress response, and cholesterol homeostasis in liver.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"136 21","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13722394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149321709","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":"Pulmonary arterial hypertension-associated cerebellar impairment extends evidence linking cardiometabolic and neurodegenerative diseases.","authors":"Michael W Schwartz, Karin E Bornfeldt","doi":"10.1172/JCI212006","DOIUrl":"https://doi.org/10.1172/JCI212006","url":null,"abstract":"<p><p>Growing evidence shows that the risk of cognitive impairment is increased across a range of metabolic and cardiovascular diseases, but underlying mechanisms remain poorly understood. One possibility involves activation of microglia, a glial cell type of the central nervous system with morphological and transcriptional features comparable to resident macrophages in other tissues that plays specialized roles in supporting neuronal and brain function. Combining clinical investigation in pulmonary arterial hypertension (PAH) cohorts with mouse model and microglial cell culture studies, a study by Okawa, Shi, and colleagues in this issue of the JCI adds compelling, albeit indirect, evidence linking impaired lysosomal lipid handling in both endothelial cells and microglia to a specific neurological disorder associated with PAH. The findings open opportunities for understanding how cardiopulmonary disease predisposes to neurodegeneration.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"136 21","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13722385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149321710","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":"B cells and the therapeutic index of checkpoint blockade.","authors":"Chuan-Yuan Li","doi":"10.1172/JCI212237","DOIUrl":"https://doi.org/10.1172/JCI212237","url":null,"abstract":"<p><p>Combined CTLA-4 and PD-1 blockade is effective in treating melanoma and additional cancers but frequently causes immune-related adverse events (irAEs). irAEs cause treatment disruption and discontinuation and remain difficult to manage clinically. In this issue, Dhodapkar and colleagues assessed data from a small randomized clinical trial testing rituximab-mediated B cell depletion in combined CTLA-4/PD-1 blockade-treated patients with advanced melanoma. Despite premature discontinuation of the trial due to a high rate of rituximab hypersensitivity, they report that preemptive B cell depletion was associated with fewer severe toxicities without evident loss of antitumor activity. These findings raise broader questions about the organization of checkpoint-induced autoimmunity, the emerging concept of immune reset, and the compartment-specific roles of B cells in antitumor immunity.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"136 21","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13722386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149321699","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":"Beyond motor rescue: defining adequate SMN restoration in spinal muscular atrophy.","authors":"Crystal Jing Jing Yeo","doi":"10.1172/JCI211991","DOIUrl":"https://doi.org/10.1172/JCI211991","url":null,"abstract":"<p><p>Spinal muscular atrophy (SMA) is characterized by motor neuron degeneration due to deficiency in the survival of motor neuron (SMN) protein. Disease-modifying therapies have transformed outcomes in SMA, while also revealing an increasingly complex spectrum of residual disease biology. In this issue of the JCI, Tapken, Rahmel-Stein, and colleagues demonstrated cell-specific SMN expression and persistent alterations in peripheral immune cell populations in nusinersen- or risdiplam-treated adults with SMA. Their findings extend the question of selective vulnerability beyond motor neurons and raise an increasingly important therapeutic question: What constitutes adequate SMN restoration? This Commentary considers how cell type, developmental timing, SMN requirement, and downstream response may shape treatment-modified SMA, with implications for systemic and CNS-directed therapies.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"136 21","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13722389/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149321700","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":"Cell state programs offer a potential axis for classifying neuroendocrine tumors.","authors":"Parambir S Dulai","doi":"10.1172/JCI213026","DOIUrl":"https://doi.org/10.1172/JCI213026","url":null,"abstract":"<p><p>Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) arise from hormone-producing cells in the gut and pancreas. Despite increasing incidence of these tumors, therapeutic options remain limited. Well-differentiated GEP-NETs are classified by anatomic site, morphology, and proliferation indices, but this approach offers limited prognostic resolution among phenotypically similar tumors and constrains personalization of treatment decisions. In this issue of the JCI, Karam, Hoffman, and colleagues profiled 38 pancreatic and small-intestinal NETs using joint single-nucleus RNA and ATAC sequencing and projected the resulting malignant cell-associated programs onto matched spatial transcriptomes. Two conserved malignant states emerged: neuronal-like and secretory neuroendocrine. These states span a continuum in both organ sites, are enriched for largely different transcription factor motifs, and occupy distinct microenvironmental niches. Secretory program scores trended higher in metastatic disease and may carry prognostic value. Taken together, these data describe NET heterogeneity as a cell state axis linked to tissue architecture.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"136 21","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13722403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149321701","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}