The Journal of Clinical Investigation最新文献

{"title":"PTBP1 variants displaying altered nucleocytoplasmic distribution are responsible for a neurodevelopmental disorder with skeletal dysplasia.","authors":"Aymeric Masson,Julien Paccaud,Martina Orefice,Estelle Colin,Outi Mäkitie,Valérie Cormier-Daire,Raissa Relator,Sourav Ghosh,Jean-Marc Strub,Christine Schaeffer-Reiss,Carlo Marcelis,David A Koolen,Rolph Pfundt,Elke de Boer,Lisenka Elm Vissers,Thatjana Gardeitchik,Lonneke Am Aarts,Tuula Rinne,Paulien A Terhal,Nienke E Verbeek,Linda C Zuurbier,Astrid S Plomp,Marja W Wessels,Stella A de Man,Arjan Bouman,Lynne M Bird,Reem Saadeh-Haddad,Maria J Guillen Sacoto,Richard Person,Catherine Gooch,Anna Ce Hurst,Michelle L Thompson,Susan M Hiatt,Rebecca O Littlejohn,Elizabeth R Roeder,Mari Mori,Scott Hickey,Jesse M Hunter,Kristy Lee,Khaled Osman,Rana Halloun,Ruxandra Bachmann-Gagescu,Anita Rauch,Dagmar Wieczorek,Konrad Platzer,Johannes Luppe,Laurence Duplomb-Jego,Fatima El It,Yannis Duffourd,Frédéric Tran Mau-Them,Celine Huber,Christopher T Gordon,Fulya Taylan,Riikka E Mäkitie,Alice Costantini,Helena Valta,Stephen Robertson,Gemma Poke,Michel Francoise,Andrea Ciolfi,Marco Tartaglia,Nina Ekhilevitch,Rinat Zaid,Michael A Levy,Jennifer Kerkhof,Haley McConkey,Julian Delanne,Martin Chevarin,Valentin Vautrot,Valentin Bourgeois,Sylvie Nguyen,Nathalie Marle,Patrick Callier,Hana Safraou,Angela Morgan,David J Amor,Michael Hildebrand,David Coman,Marion Aubert Mucca,Julien Thevenon,Fanny Laffargue,Frédéric Bilan,Céline Pebrel-Richard,Grace Yoon,Michelle M Axford,Luis A Pérez-Jurado,Marta Sevilla-Porras,Douglas Black,Christophe Philippe,Bekim Sadikovic,Christel Thauvin-Robinet,Laurence Olivier-Faivre,Michela Ori,Quentin Thomas,Antonio Vitobello","doi":"10.1172/jci182100","DOIUrl":"https://doi.org/10.1172/jci182100","url":null,"abstract":"Polypyrimidine tract-binding protein PTBP1 is a heterogeneous nuclear ribonucleoprotein primarily known for its alternative splicing activity. It shuttles between the nucleus and cytoplasm via partially overlapping N-terminal nuclear localization (NLS) and export (NES) signals. Despite its fundamental role in cell growth and differentiation, its involvement in human disease remains poorly understood. We identified 27 individuals from 25 families harboring de novo or inherited pathogenic variants - predominantly start-loss (89%) and, to a lesser extent, missense (11%) - affecting NES/NLS motifs. Affected individual presented with a syndromic neurodevelopmental disorder and variable skeletal dysplasia with disproportionate short-limbed short stature. Intellectual functioning ranged from normal to moderately delayed. Start-loss variants led to translation initiation from an alternative downstream in-frame methionine, resulting in loss of the NES and the first half of the bipartite NLS, and increased cytoplasmic stability. Start-loss and missense variants shared a DNA methylation episignature in peripheral blood and altered nucleocytoplasmic distribution in vitro and in vivo with preferential accumulation in processing bodies, causing aberrant gene expression but normal RNA splicing. Transcriptomic analysis of patient-derived fibroblasts revealed dysregulated pathways involved in osteochondrogenesis and neurodevelopment. Overall, our findings highlight a cytoplasmic role for PTBP1 in RNA stability and disease pathogenesis.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083472","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":"NR2F1 and mTORC1 provide the bridge between melanoma dormancy and therapeutic resistance.","authors":"Narsimha Mamidi,Swadesh K Das,Paul B Fisher","doi":"10.1172/jci197764","DOIUrl":"https://doi.org/10.1172/jci197764","url":null,"abstract":"Cutaneous melanoma (CM) is known for its aggressive behavior, high metastatic potential, and poor prognosis. Mutations in the BRAF gene are common in CM, and patients with BRAF-mutant melanoma often respond well to combined inhibition of BRAF and MEK (BRAFi + MEKi). Although BRAFi + MEKi therapy provides clinical efficacy, the response durability is limited by persistent drug-tolerant residual cells, culminating in relapse. In this issue of the JCI, Tiago et al. confirmed that NR2F1, a dormancy-associated transcription factor, is a key determinant of therapeutic resistance in melanoma. NR2F1 expression was elevated in transcriptomic datasets from patients with minimal residual disease, and in murine and human melanoma models, NR2F1 overexpression reduced therapeutic efficacy and suppressed tumor proliferation and invasion while sustaining mechanistic target of rapamycin complex 1 (mTORC1) transcriptional regulation of relevant genes. Combining BRAFi + MEKi with the mTORC1 inhibitor rapamycin effectively targeted these resistant melanoma cells, suggesting a potential path forward for targeting NR2F1 and mTORC1 signaling in patients with CM.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"73 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068429","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":"Dissecting the mechanisms of MASLD fibrosis in the era of single-cell and spatial omics.","authors":"Fabio Colella,Neil C Henderson,Prakash Ramachandran","doi":"10.1172/jci186421","DOIUrl":"https://doi.org/10.1172/jci186421","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD), now the most common cause of chronic liver disease, is estimated to affect around 30% of the global population. In MASLD, chronic liver injury can result in scarring or fibrosis, with the degree of fibrosis being the best-known predictor of adverse clinical outcomes. Hence, there is huge interest in developing new therapies to inhibit or reverse fibrosis in MASLD. However, this has been challenging to achieve, as the biology of fibrosis and candidate antifibrotic therapeutic targets have remained poorly described in patient samples. In recent years, the advent of single-cell and spatial omics approaches that can be applied to human samples have started to transform our understanding of fibrosis biology in MASLD. In this Review, we describe these technological advances and discuss the new insights such studies have provided, focusing on the role of epithelial cell plasticity, mesenchymal cell activation, scar-associated macrophage accumulation, and inflammatory cell stimulation as regulators of liver fibrosis. We also consider how omics techniques can enhance our understanding of evolving concepts in the field, such as hot versus cold fibrosis and the mechanisms of liver fibrosis regression. Finally, we touch on future developments and how they are likely to inform a more mechanistic understanding about how fibrosis might differ between patients and how this could influence optimal therapeutic approaches.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"65 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068425","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 pathogenesis of hepatic steatosis in MASLD: a lipid droplet perspective.","authors":"Natalie Krahmer,Tobias C Walther,Robert V Farese","doi":"10.1172/jci198334","DOIUrl":"https://doi.org/10.1172/jci198334","url":null,"abstract":"","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068424","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":"Blocking extracellular glycine uptake mediated by GlyT1 mitigates protoporphyria.","authors":"Marc Liesa","doi":"10.1172/jci197344","DOIUrl":"https://doi.org/10.1172/jci197344","url":null,"abstract":"Accumulation of the light-reactive heme precursor protoporphyrin IX (PPIX) in blood causes protoporphyria, a disease characterized by severe pain resulting from sunlight exposure, as well as by the occurrence of liver failure in some patients. Thus, decreasing PPIX biosynthesis is a promising strategy to treat protoporphyria. In this issue of the JCI, Ducamp et al. report that inhibition of the glycine plasma membrane transporter GLYT1 using bitopertin decreased PPIX accumulation and ameliorated liver disease using human in vitro and mouse in vivo models. Their findings support the ongoing development of bitopertin to treat protoporphyria, while concurrently pointing to underexplored roles of glycine in erythroid cells.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068427","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":"Endothelial STING and STAT1 mediate interferon-independent effects of IL-6 in an endotoxemia-induced model of shock.","authors":"Nina Martino,Erin K Sanders,Ramon Bossardi Ramos,Iria Di John Portela,Fatma Awadalla,Shuhan Lu,Dareen Chuy,Neil Poddar,Mei Xing G Zuo,Uma Balasubramanian,Peter A Vincent,Pilar Alcaide,Alejandro P Adam","doi":"10.1172/jci189570","DOIUrl":"https://doi.org/10.1172/jci189570","url":null,"abstract":"Severe systemic inflammatory reactions, including sepsis, often lead to shock, organ failure and death, in part through an acute release of cytokines that promote vascular dysfunction. However, little is known about the vascular endothelial signaling pathways regulating the transcriptional profile in failing organs. This work focuses on signaling downstream of IL-6, due to its clinical importance as a biomarker for disease severity and predictor of mortality. Here, we show that loss of endothelial expression of the IL-6 pathway inhibitor, SOCS3, promoted a type I interferon (IFNI)-like gene signature in response to endotoxemia in mouse kidneys and brains. In cultured primary human endothelial cells, IL-6 induced a transient IFNI-like gene expression in a non-canonical, interferon-independent fashion. We further show that STAT3, which we had previously shown to control IL-6-driven endothelial barrier function, was dispensable for this activity. Instead, IL-6 promoted a transient increase in cytosolic mitochondrial DNA and required STAT1, cGAS, STING, and the IRFs 1, 3, and 4. Inhibition of this pathway in endothelial-specific STING knockout mice or global STAT1 knockout mice led to reduced severity of an acute endotoxemic challenge and prevented the endotoxin-induced IFNI-like gene signature. These results suggest that permeability and DNA sensing responses are driven by parallel pathways downstream of this cytokine, provide new insights into the complex response to acute inflammatory responses, and offer the possibility of potential novel therapeutic strategies for independently controlling the intracellular responses to IL-6 in order to tailor the inflammatory response.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071654","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":"A liver-infiltrating CD4+ Tfh1 cell response predicts HCV control, hepatitis, and seroconversion during acute infection.","authors":"Heather Blasczyk,William G Bremer,Christopher C Phelps,Yan Zhou,David G Bowen,Zhaohui Xu,Robert E Lanford,Naglaa H Shoukry,Arash Grakoui,Nicole E Skinner,Christopher M Walker","doi":"10.1172/jci178089","DOIUrl":"https://doi.org/10.1172/jci178089","url":null,"abstract":"Sustained CD4+ T cell immunity is required for resolution of acute hepatitis C virus (HCV) infection but the response remains poorly characterized. Here, circulating CD4+ T cells with high PD-1 and ICOS co-expression were temporally associated with onset of virus control, seroconversion, and hepatitis in HCV-infected chimpanzees. Co-production of Tfh (IL-21, CXCL13) and Th1 (IFN-γ, TNF) cytokines after stimulation with HCV non-structural proteins demonstrated that the response was predominately Tfh1-like and virus-specific. Transcriptional analysis confirmed a Tfh1 lineage assignment. Effector-related genes such as ADGRG1 (GPR56), ZNF683 (Hobit), and KLRB1 (CD161) were also expressed. HCV-specific PD-1hiICOShi CD4+ Tfh1-like cells were enriched in liver, suggesting the potential for B and CD8+ T cell help at the site of virus replication. Most circulating and intrahepatic PD-1hiICOShi CD4+ Tfh1-like cells did not express CXCR5, and therefore resembled CXCR5-negative CXCL13-positive peripheral helper (Tph) cells that infiltrate tumors and tissues inflamed by autoimmunity. PD-1hiICOShi CD4+ cells also peaked after hepatitis A virus infection, but the response was accelerated by several weeks when compared with HCV infection. The PD-1hiICOShi phenotype, and temporal association between the peak response and ALT, may provide markers to guide human studies of CD4+ T cell immunity against HCV and other hepatotropic viruses.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071659","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":"Antithrombin-binding heparan sulfate is ubiquitously expressed in epithelial cells and suppresses pancreatic tumorigenesis.","authors":"Thomas Mandel Clausen,Ryan J Weiss,Jacob R Tremblay,Benjamin P Kellman,Joanna Coker,Leo A Dworkin,Jessica P Rodriguez,Ivy M Chang,Timothy Chen,Vikram Padala,Richard Karlsson,Hyemin Song,Kristina L Peck,Satoshi Ogawa,Daniel R Sandoval,Hiren J Joshi,Gaowei Wang,L Paige Ferguson,Nikita Bhalerao,Allison Moores,Tannishtha Reya,Maike Sander,Thomas C Caffrey,Jean L Grem,Alexandra Aicher,Christopher Heeschen,Dzung Le,Nathan E Lewis,Michael A Hollingsworth,Paul M Grandgenett,Susan L Bellis,Rebecca L Miller,Mark M Fuster,David W Dawson,Dannielle D Engle,Jeffrey D Esko","doi":"10.1172/jci184172","DOIUrl":"https://doi.org/10.1172/jci184172","url":null,"abstract":"3-O-sulfation of heparan sulfate (HS) is the key determinant for binding and activation of Antithrombin III (AT). This interaction is the basis of heparin treatment to prevent thrombotic events and excess coagulation. Antithrombin-binding HS (HSAT) is expressed in human tissues, but is thought to be expressed in the subendothelial space, mast cells, and follicular fluid. Here we show that HSAT is ubiquitously expressed in the basement membranes of epithelial cells in multiple tissues. In the pancreas, HSAT is expressed by healthy ductal cells and its expression is increased in premalignant pancreatic intraepithelial neoplasia lesions (PanINs), but not in pancreatic ductal adenocarcinoma (PDAC). Inactivation of HS3ST1, a key enzyme in HSAT synthesis, in PDAC cells eliminated HSAT expression, induced an inflammatory phenotype, suppressed markers of apoptosis, and increased metastasis in an experimental mouse PDAC model. HSAT-positive PDAC cells bind AT, which inhibits the generation of active thrombin by tissue factor (TF) and Factor VIIa. Furthermore, plasma from PDAC patients showed accumulation of HSAT suggesting its potential as a marker of tumor formation. These findings suggest that HSAT exerts a tumor suppressing function through recruitment of AT and that the decrease in HSAT during progression of pancreatic tumorigenesis increases inflammation and metastatic potential.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"38 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018117","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 functionally conserved human lncRNA motif GULF lowers glucose and lipid levels in obese mice.","authors":"Zhe Li,Sunmi Seok,Chengfei Jiang,Ping Li,Yonghe Ma,Hang Sun,Haiming Cao","doi":"10.1172/jci186355","DOIUrl":"https://doi.org/10.1172/jci186355","url":null,"abstract":"Growing evidence links human long noncoding RNAs (lncRNAs) to metabolic disease pathogenesis, yet no FDA-approved drugs target human lncRNAs. Most human lncRNAs lack conservation in other mammals, complicating efforts to define their roles and identify therapeutic targets. Here, we leveraged the concept of functionally conserved lncRNAs (FCLs) - lncRNAs that share function despite no sequence similarity - to develop a framework for identifying human lncRNAs as therapeutic targets for metabolic disorders. We used expression quantitative trait loci mapping and functional conservation analyses to pinpoint human lncRNAs influenced by disease-associated SNPs and with potential functionally conserved mouse equivalents. We identified human and mouse GULLs (glucose and lipid lowering), which regulate glucose and lipid metabolism by binding CRTC2, thereby modulating gluconeogenic genes via CREB and lipogenic genes via SREBP1. Despite their lack of sequence similarity, both lncRNAs demonstrated similar metabolic effects in obese mice, with more pronounced benefits from long-term activation. To identify druggable sites, we mapped GULLs' binding motifs to CRTC2 (termed GULFs). Standalone human GULF, an RNA oligomer resembling FDA-approved siRNAs, significantly improved glucose and lipid levels in obese mice. This framework highlights functionally conserved human lncRNAs as promising therapeutic targets, exemplified by GULLs' potential as a glucose- and lipid-lowering therapeutic.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"96 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068423","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":"MASH: the nexus of metabolism, inflammation, and fibrosis.","authors":"Gregory R Steinberg,Andre C Carpentier,Dongdong Wang","doi":"10.1172/jci186420","DOIUrl":"https://doi.org/10.1172/jci186420","url":null,"abstract":"Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive form of liver disease characterized by hepatocyte injury, inflammation, and fibrosis. The transition from metabolic dysfunction-associated steatotic liver disease (MASLD) to MASH is driven by the accumulation of toxic lipid and metabolic intermediates resulting from increased hepatic uptake of fatty acids, elevated de novo lipogenesis, and impaired mitochondrial oxidation. These changes promote hepatocyte stress and cell death, activate macrophages, and induce a fibrogenic phenotype in hepatic stellate cells (HSCs). Key metabolites, including saturated fatty acids, free cholesterol, ceramides, lactate, and succinate, act as paracrine signals that reinforce inflammatory and fibrotic responses across multiple liver cell types. Crosstalk between hepatocytes, macrophages, and HSCs, along with spatial shifts in mitochondrial activity, creates a feed-forward cycle of immune activation and tissue remodeling. Systemic inputs, such as insulin-resistant adipose tissue and impaired clearance of dietary lipids and branched-chain amino acids, further contribute to liver injury. Together, these pathways establish a metabolically driven network linking nutrient excess to chronic liver inflammation and fibrosis. This Review outlines how coordinated disruptions in lipid metabolism and intercellular signaling drive MASH pathogenesis and provides a framework for understanding disease progression across tissue and cellular compartments.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068428","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}