The Journal of Clinical Investigation最新文献

{"title":"Endothelial gateways for brain lipid uptake and metabolism.","authors":"A Dushani Ranasinghe,Timothy Hla","doi":"10.1172/jci198352","DOIUrl":"https://doi.org/10.1172/jci198352","url":null,"abstract":"Lipids, which constitute half of the brain's solid matter, are essential for forming specialized membranes of neural cells, providing energy sources, and facilitating cell-to-cell communication. Although the blood-brain barrier restricts lipid movement between peripheral circulation and the brain, multiple mechanisms supply the building blocks necessary to synthesize the diverse lipid species present in the central nervous system (CNS). In this issue of the JCI, Song et al. characterize specialized microvascular niches that metabolize circulating triglyceride-rich lipoproteins (TRLs) to deliver fatty acids into the brain. They located GPIHBP1, an essential chaperone for lipoprotein lipase (LPL) in the fenestrated endothelial cells of the choroid plexus (ChP) and circumventricular organs (CVOs), demonstrating lipolytic processing of peripheral TRLs and brain uptake of fatty acids. This advance implicates the GPIHBP1/LPL lipid metabolic hub in supporting the roles of the ChP and CVO in cerebrospinal fluid composition, immunity, satiety, thirst, and metabolic homeostasis.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophage transition to a myofibroblast state drives fibrotic disease in uropathogenic E. coli-induced epididymo-orchitis.","authors":"Ming Wang,Xu Chu,Zhongyu Fan,Lin Chen,Huafei Wang,Peng Wang,Zihao Wang,Yiming Zhang,Yihao Du,Sudhanshu Bhushan,Zhengguo Zhang","doi":"10.1172/jci193793","DOIUrl":"https://doi.org/10.1172/jci193793","url":null,"abstract":"Bacterial infections, particularly uropathogenic E. coli (UPEC), contribute substantially to male infertility through tissue damage and subsequent fibrosis in the testis and epididymis. The role of testicular macrophages (TMs), a diverse cell population integral to tissue maintenance and immune balance, in fibrosis is not fully understood. Here, we used single-cell RNA sequencing in a murine model of epididymo-orchitis to analyze TM dynamics during UPEC infection. Our study identified a marked increase in S100a4+ macrophages, originating from monocytes, strongly associated with fibrotic changes. This association was validated in human testicular and epididymal samples. We further demonstrated that S100a4+ macrophages transition to a myofibroblast-like phenotype, producing extracellular matrix proteins such as collagen I and fibronectin. S100a4, both extracellular and intracellular, activated collagen synthesis through the TGF-β/STAT3 signaling pathway, highlighting this pathway as a therapeutic target. Inhibition of S100a4 with niclosamide or macrophage-specific S100a4 KO markedly reduced immune infiltration, tissue damage, and fibrosis in infected murine models. Our findings establish the critical role of S100a4+ macrophages in fibrosis during UPEC-induced epididymo-orchitis and propose them as potential targets for antifibrotic therapy development.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SIRT2 puts the brakes on human β cell proliferation: therapeutic opportunities and next challenges.","authors":"Liora S Katz,Donald K Scott,Andrew F Stewart","doi":"10.1172/jci197142","DOIUrl":"https://doi.org/10.1172/jci197142","url":null,"abstract":"The numbers of insulin-producing β cells in the pancreas are reduced in people with type 1 or type 2 diabetes, prompting efforts to replace these missing or lost β cells through transplant or regenerative medicine approaches. In this issue of the JCI, Wortham et al. describe a function for the deacetylase enzyme sirtuin 2 (SIRT2) in a novel pathway that acts as a brake on β cell proliferation. They show that inhibiting SIRT2 through pharmacologic or genetic approaches can induce human and mouse β cells to reenter a proliferative cell cycle. A surprising observation that remains unexplained is that the main targets of SIRT2 are mitochondrial oxidative phosphorylation (OxPhos) enzymes. It also remains unknown if and how these unanticipated acetylated OxPhos targets lead to cell-cycle entry. SIRT2 inhibitors will be a welcome addition to the growing repertoire of human β cell-regenerative drugs.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"102 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The complement system in intestinal inflammation and cancer.","authors":"Carsten Krieg,Silvia Guglietta","doi":"10.1172/jci188348","DOIUrl":"https://doi.org/10.1172/jci188348","url":null,"abstract":"The complement system has emerged as a critical regulator of intestinal homeostasis, inflammation, and cancer. In this Review, we explore the multifaceted roles of complement in the gastrointestinal tract, highlighting its canonical and noncanonical functions across intestinal epithelial and immune cells. Under homeostatic conditions, intestinal cells produce complement that maintains barrier integrity and modulates local immune responses, but complement dysregulation contributes to intestinal inflammation and promotes colon cancer. We discuss recent clinical and preclinical studies to provide a cohesive overview of how complement-mediated modulation of immune and nonimmune cell functions can protect or exacerbate inflammation and colon cancer development. The complement system plays a dual role in the intestine, with certain components supporting tissue protection and repair and others exacerbating inflammation. Intriguingly, distinct complement pathways modulate colon cancer progression and response to therapy, with novel findings suggesting that the C3a/C3aR axis constrains early tumor development but may limit antitumor immunity. The recent discovery of intracellular complement activation and tissue-specific complement remains vastly underexplored in the context of intestinal inflammation and colon cancer. Collectively, complement functions are context- and cell-type-dependent, acting both as a shield and a sword in intestinal diseases. Future studies dissecting the temporal and spatial dynamics of complement are essential for leveraging its potential as a biomarker and therapeutic in colon cancer.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"103 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic adjusted radiation dose stratifies radiotherapy dosing based on tumor-specific sensitivity in HPV+ oropharyngeal cancer.","authors":"Sandip K Rath,David S Yu","doi":"10.1172/jci198351","DOIUrl":"https://doi.org/10.1172/jci198351","url":null,"abstract":"Uniform radiation therapy (RT) de-escalation in HPV+ oropharyngeal squamous cell carcinoma (OPSCC) has underperformed in clinical trials, likely due to underlying genomic heterogeneity. In this issue of the JCI, Ho et al. evaluated genomic adjusted radiation dose (GARD), which integrates tumor gene expression with RT dose to estimate biological effect. In 191 locoregionally advanced HPV+ OPSCC patients treated with definitive RT with or without chemotherapy, GARD values varied widely, despite uniform dose delivery, and independently predicted overall survival. These data support a genomically informed framework specific for HPV+ OPSCC patients via GARD for guiding radiation dose de-escalation strategies.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SOX9 drives a stem-like transcriptional state and platinum resistance in high-grade serous ovarian cancer.","authors":"Alexander J Duval,Fidan Seker-Polat,Magdalena Rogozinska,Meric Kinali,Ann E Walts,Ozlem Neyisci,Yaqi Zhang,Zhonglin Li,Edward J Tanner,Allison E Grubbs,Sandra Orsulic,Daniela Matei,Mazhar Adli","doi":"10.1172/jci186467","DOIUrl":"https://doi.org/10.1172/jci186467","url":null,"abstract":"Chemotherapy resistance remains a formidable challenge to the treatment of high-grade serous ovarian cancer (HGSOC). The drug-tolerant cells may originate from a small population of inherently resistant cancer stem cells (CSCs) in primary tumors. In contrast, sufficient evidence suggests that drug tolerance can also be transiently acquired by nonstem cancer cells. Regardless of the route, key regulators of this plastic process are poorly understood. Here, we utilized multiomics, tumor microarrays, and epigenetic modulation to demonstrate that SOX9 is a key chemo-induced driver of chemoresistance in HGSOC. Epigenetic upregulation of SOX9 was sufficient to induce chemoresistance in multiple HGSOC lines. Moreover, this upregulation induced the formation of a stem-like subpopulation and significant chemoresistance in vivo. Mechanistically, SOX9 increased transcriptional divergence, reprogramming the transcriptional state of naive cells into a stem-like state. Supporting this, we identified a rare cluster of SOX9-expressing cells in primary tumors that were highly enriched for CSCs and chemoresistance-associated stress gene modules. Notably, single-cell analysis showed that chemo treatment results in rapid population-level induction of SOX9 that enriches for a stem-like transcriptional state. Altogether, these findings implicate SOX9 as a critical regulator of early steps of transcriptional reprogramming that lead to chemoresistance through a CSC-like state in HGSOC.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Personalized treatment in HPV+ oropharynx cancer using genomic adjusted radiation dose.","authors":"Emily Ho,Loris De Cecco,Steven A Eschrich,Stefano Cavalieri,Geoffrey Sedor,Frank Hoebers,Ruud H Brakenhoff,Kathrin Scheckenbach,Tito Poli,Kailin Yang,Jessica A Scarborough,Shivani Nellore,Shauna Campbell,Neil Woody,Tim Chan,Jacob Miller,Natalie Silver,Shlomo Koyfman,James Bates,Jimmy J Caudell,Michael W Kattan,Lisa Licitra,Javier F Torres-Roca,Jacob G Scott","doi":"10.1172/jci194073","DOIUrl":"https://doi.org/10.1172/jci194073","url":null,"abstract":"BACKGROUNDA key objective in managing HPV+ oropharyngeal squamous cell carcinoma (OPSCC) is reducing radiation therapy (RT) doses without compromising cure rates. A recent phase II/III HN005 trial revealed that clinical factors alone are insufficient to guide safe RT dose de-escalation. Our prior research demonstrated that the genomic adjusted radiation dose (GARD) predicts RT benefit and may inform dose selection. We hypothesize that GARD can guide personalized RT de-escalation in HPV+ OPSCC patients.METHODSGene expression profiles were analyzed in 191 HPV+ OPSCC patients enrolled in an international, multi-institutional observational study (AJCC Eighth Edition, stages I-III). Most patients received 70 Gy in 35 fractions or 69.96 Gy in 33 fractions (median dose: 70 Gy; range: 51.0-74.0 Gy). Overall survival (OS) was 94.1% at 36 months and 87.3% at 60 months. A Cox proportional hazards model assessed association between GARD and OS, and time-dependent receiver operating characteristic analyses compared GARD with traditional clinical predictors.RESULTSDespite uniform RT dosing, GARD showed wide heterogeneity, ranging from 15.4 to 71.7. Higher GARD values were significantly associated with improved OS in univariate (HR = 0.941, P = 0.041) and multivariable analyses (HR = 0.943, P = 0.046), while T and N stages were not. GARD demonstrated superior predictive performance at 36 months (AUC = 78.26) versus clinical variables (AUC = 71.20). Two GARD-based RT de-escalation strategies were identified, offering potential survival benefits while reducing radiation exposure.CONCLUSIONGARD predicts OS and outperforms clinical variables, supporting its integration into the diagnostic workflow for personalized RT in HPV+ OPSCC.FUNDINGThis work was supported by the National Cancer Institute through the Cleveland Clinic/Emory ROBIN center (U54-CA274513, project 2), the European Union Horizon 2020 Framework Programme (grant/award 689715), the Italian Association for Cancer Research (AIRC project ID 23573), and the European Research Area Network ERA PerMed JTC2019/Fondazione Regionale per la Ricerca Biomedica project SuPerTreat (Supporting Personalized Treatment Decisions in Head and Neck Cancer through Big Data).","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"4565 3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SGLT2 inhibition protects kidney function by SAM-dependent epigenetic repression of inflammatory genes under metabolic stress.","authors":"Hiroshi Maekawa,Yalu Zhou,Yuki Aoi,Margaret E Fain,Dorian S Kaminski,Hyewon Kong,Zachary L Sebo,Ram P Chakrabarty,Benjamin C Howard,Grant Andersen,Biliana Marcheva,Peng Gao,Pinelopi Kapitsinou,Joseph Bass,Ali Shilatifard,Navdeep S Chandel,Susan E Quaggin","doi":"10.1172/jci188933","DOIUrl":"https://doi.org/10.1172/jci188933","url":null,"abstract":"Clinically, blockade of renal glucose resorption by sodium-glucose cotransporter 2 (SGLT2) inhibitors slows progression of kidney disease, yet the underlying mechanisms are not fully understood. We hypothesized that altered renal metabolites underlie observed kidney protection when SGLT2 function is lost. S-adenosylmethionine (SAM) levels were increased in kidneys from mice lacking SGLT2 function on a diabetogenic high-fat diet (SPHFD) compared with WT mice fed HFD. Elevated SAM in SPHFD was associated with improved kidney function and decreased expression of NF-κB pathway-related genes. Injured proximal tubular cells that emerged under HFD conditions in WT mice and humans consistently showed reduction in expression of the SAM synthetase Mat2a/MAT2A, while MAT2A inhibition, which reduces SAM production, abrogated kidney protection in SPHFD mice. Histone H3 lysine 27 (H3K27) repressive trimethylation of NF-κB-related genes was increased in SPHFD, consistent with SAM's role as a methyl donor. Our data support a model whereby SGLT2 loss enhances SAM levels within the kidney, leading to epigenetic repression of inflammatory genes and kidney protection under metabolic stress.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perturbation of the circadian clock in chronic diseases involving organ fibrosis.","authors":"Atish Mukherji,Pierre-Louis Tharaux,David W Ray,Thomas F Baumert","doi":"10.1172/jci194018","DOIUrl":"https://doi.org/10.1172/jci194018","url":null,"abstract":"Chronic organ disease is often complicated by fibrosis, the excessive accumulation of extracellular matrix, as a consequence of dysfunctional wound healing responses. Fibrosis progressively distorts tissue architecture and eventually leads to loss of organ function, accounting for up to 45% of deaths in developed countries. Moreover, fibrosis is a major risk factor for tumor development. The few approved therapies aimed at preventing or resolving fibrosis show limited efficacy and safety. One reason for the lack of efficient antifibrotic therapies is the fact that the cell circuits driving the disease biology are still only partially understood. The circadian clock is known to regulate the physiological functions of critical organs, including the liver, kidneys, and lungs. Several experimental and clinical studies have established that circadian disruption plays an important role in the development of chronic diseases across organs involving fibrosis. These include metabolic dysfunction-associated steatotic liver disease, chronic kidney disease, and chronic obstructive pulmonary disease. Here, we provide an overview of the circadian mechanisms that play critical roles in mediating physiological functions in the liver, kidneys, and lungs and whose deregulations could predispose toward development of chronic disease of these organs, leading to fibrosis. We also highlight the possible opportunities of chronotherapy for chronic diseases and discuss future perspectives.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging roles for complement in lung transplantation.","authors":"Hrishikesh S Kulkarni,John A Belperio,Carl Atkinson","doi":"10.1172/jci188346","DOIUrl":"https://doi.org/10.1172/jci188346","url":null,"abstract":"The complement system is an evolutionarily conserved host defense system that has evolved from invertebrates to mammals. Over time, this system has become increasingly appreciated as having effects beyond purely bacterial clearance, with clinically relevant implications in transplantation, particularly lung transplantation. For many years, complement activation in lung transplantation was largely focused on antibody-mediated injuries. However, recent studies have highlighted the importance of both canonical and noncanonical complement activation in shaping adaptive immune responses, which influence alloimmunity. These studies, together with the emergence of FDA-approved complement therapeutics and other drugs in the pipeline that function at different points of the cascade, have led to an increased interest in regulating the complement system to improve donor organ availability as well as improving both short- and long-term outcomes after lung transplantation. In this Review, we provide an overview of the when, what, and how of complement in lung transplantation, posing the questions of: when does complement activation occur, what components of the complement system are activated, and how can this activation be controlled? We conclude that complement activation occurs at multiple stages of the transplant process and that randomized controlled trials will be necessary to realize the therapeutic potential of neutralizing this activation to improve outcomes after lung transplantation.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}