The Journal of Clinical Investigation最新文献

{"title":"Western diet induces iron-dependent enteric neurodegeneration via ferroptosis.","authors":"Arun Balasubramaniam,Dmitrii Pavlov,Yunpeng Du,Jeremy Reeves,Alan Harzman,Yunshan Liu,Francesca Cingolani,Xinxu Yuan,Jay M Patel,Simon Musyoka Mwangi,Peijian He,C Michael Hart,Wenhui Hu,Fievos L Christofi,Shanthi Srinivasan","doi":"10.1172/jci196113","DOIUrl":"https://doi.org/10.1172/jci196113","url":null,"abstract":"Western diets (WD), high in saturated fats such as palmitic acid (PA), promote enteric neurodegeneration and motility disorders. Using murine models, in vitro systems, and human myenteric ganglia, we investigated whether WD and PA drive iron-dependent ferroptotic injury in the enteric nervous system. Mice were fed control diet (CD) or WD for 12 weeks, with or without systemic AAV9-MaCPNS2 delivery of Nfe2l2 to enteric neurons. Colonic motility was assessed by bead-expulsion assay. Ferroptosis was assessed using convergent readouts including iron dysregulation (TfR1, FTH-1, labile and mitochondrial Fe2+), lipid peroxidation (C11-BODIPY and 4-HNE), GPX4 suppression, and pharmacologic inhibition by ferrostatin-1 (Fer-1) in primary enteric neurons, murine myenteric plexuses, and human networks of myenteric ganglia (nhMPG). WD-fed mice exhibited delayed colonic transit, increased TfR1 and FTH-1, and vulnerability of nNOS neurons; these changes were reversed by Nfe2l2 overexpression. RNA-seq of PA-treated IM-FEN neuronal cells revealed disrupted of neurotransmitter signaling, reduced mitochondrial and antioxidant programs, and increased iron import and lipid peroxidation signatures. PA increased labile iron, mitochondrial ROS, membrane depolarization, Ca2+ dysregulation, 4-HNE, and Mfrn2, while Fer-1 preserved mitochondrial integrity, viability, and ENS function. In human nhMPG, PA induced enteric neuronal iron loading and ferroptosis, supporting translational relevance to diet-associated enteric neuropathy.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"127 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147731268","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":"Lipoprotein(a)-Associated Proteomic Signature Predicts Cardiovascular Disease in Young Adults.","authors":"Sascha N Goonewardena,Shanshan Yao,Tomasz Jurga,Lanyue Zhang,Donald Lloyd-Jones,Dilna Damodaran,Bharat Thyagarajan,David R Jacobs,Supriya Shore,Eric J Brandt,Clary Clish,Kahraman Tanriverdi,Jane E Freedman,Chirag J Patel,Mark A Sarzynski,Brian T Emmer,John T Wilkins,Ron Do,Vera Bittner,Ravi Shah,Marios K Georgakis,Robert S Rosenson,Venkatesh Murthy","doi":"10.1172/jci204287","DOIUrl":"https://doi.org/10.1172/jci204287","url":null,"abstract":"BACKGROUNDElevated lipoprotein(a) [Lp(a)] is associated with a higher risk of atherosclerotic cardiovascular disease (ASCVD). Although Lp(a) is a genetically determined risk factor, the plasma proteomic features associated with Lp(a) and whether they provide information about ASCVD risk beyond Lp(a) concentration are not well characterized.OBJECTIVEWe sought to identify plasma proteomic features associated with Lp(a) concentration and to evaluate whether an Lp(a)-associated proteomic signature is associated with ASCVD phenotypes in young, healthy adults.METHODSIn the Coronary Artery Risk Development in Young Adults (CARDIA) study, we measured Year 7 Lp(a) and 184 cardiovascular proteins using the Olink proximity extension assay in 3,920 participants without prior coronary heart disease. Lp(a)-associated proteomic signatures were derived using LASSO regression in a split-sample design and tested for association with coronary artery calcification (CAC), incident CHD, and hs-CRP over 27 years of follow-up. External replication was performed in the UK Biobank (n=37,996).RESULTSLp(a) was associated with CAC (OR 1.23 [1.13-1.34]; p<0.0001) and incident CHD (HR 1.23 [1.07-1.41]; p=0.004). Lp(a) correlated with proteomic features reflecting immune activation, coagulation, and vascular dysfunction. A quantitative Lp(a) proteomic score was independently associated with incident CAC (standardized beta = 0.40, p<0.0001) and hs-CRP (standardized beta = 0.11, p = 0.00015) after adjustment for Lp(a) concentration. In the UK Biobank, a recalibrated Lp(a)-associated proteomic score was associated with CRP, incident CHD, and all-cause mortality.CONCLUSIONSIn young adults, Lp(a) is associated with distinct proteomic features that independently predict ASCVD phenotypes beyond Lp(a) concentration, generating hypotheses regarding biological pathways linked to Lp(a)-related cardiovascular risk.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147731269","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":"Expanding clones, expanding aneurysms through macrophage-to-osteoclast differentiation.","authors":"Jessica A Regan,Svati H Shah","doi":"10.1172/jci206748","DOIUrl":"https://doi.org/10.1172/jci206748","url":null,"abstract":"Abdominal aortic aneurysms (AAAs) are an age-related cause of sudden cardiac death and cardiovascular disease (CVD) morbidity with limited nonsurgical treatment options. In this issue of the JCI, Yonekawa et al. addressed the pathobiologic mechanisms of clonal hematopoiesis (CH), the age-related acquisition of expanded somatic clones in blood cells, as a potential driver of AAA. CH prevalence was high in patients being treated for AAA, and faster AAA expansion occurred over a period of one year in CH carriers. In an angiotensin II-induced model of AAA, mice carrying ten-eleven translocation 2 (Tet2) mutations (Tet2-CH) displayed accelerated AAA development and macrophage reprograming to an osteoclast-like state. Inhibition of this differentiation, targeting RANK/RANKL with FDA-approved therapies like alendronate and denosumab, suppressed aneurysmal growth. These findings suggest that macrophage-to-osteoclast differentiation may underlie the risk and progression of AAA associated with age-related CH, a mechanism that is modifiable through existing therapeutics.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"240 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147680406","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":"Peripheral vaccination-induced brain-resident memory CD8+ T cells durably protect mice against intracranial malignancy.","authors":"Madison R Mix,Cassie M Sievers,Mariah Hassert,Shravan Kumar Kannan,Lecia L Pewe,Sunny C Huang,Rui He,Cori E Fain,Mohammad Heidarian,Lisa S Hancox,Sahaana A Arumugam,Terry G Beltz,Fang Jin,Aaron J Johnson,Calvin S Carter,Noah S Butler,Aliasger K Salem,Vladimir P Badovinac,John T Harty","doi":"10.1172/jci197812","DOIUrl":"https://doi.org/10.1172/jci197812","url":null,"abstract":"Primary and metastatic brain tumors exhibit resistance to immunotherapies that demonstrate efficacy in peripheral cancer settings. While many immunotherapies aim to enhance CD8+ T cell infiltration and functionality in established tumors, identification of neoantigens support emerging immunopreventative tactics against brain cancer. Functionally potent tissue-resident memory CD8+ T cells (TRM) can be generated in the brain following peripheral infection or vaccination. However, the ability of brain TRM to prevent intracranial malignancy remains unknown. Here, mice were seeded with tumor-specific or bystander brain TRM via peripheral infection prior to depletion of circulating memory T cells (TCIRCM) and subsequent brain tumor challenge. Tumor-specific brain TRM durably protected mice against intracranial malignancy even in the absence TCIRCM. These brain TRM persisted in tumor-surviving mice and protected against a second antigen-matched challenge. Importantly, a translationally-relevant mRNA-lipid nanoparticle (LNP) vaccine phenocopied peripheral infection-induced outcomes, generating functional brain TRM that controlled tumor growth. Altogether, this work points to the utility of brain TRM in cancer immunoprevention, supporting the development of antitumor mRNA-LNP vaccines to bolster brain immunity.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"58 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147680442","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":"Hepatic glutathione depletion ameliorates MASLD through selective protein oxidation and inhibition of lipogenesis.","authors":"Xiang-Yu Liu,Guoxiao Wang,Yingying Yu,Haopeng Xiao,Kentaro Oh-Hashi,Xu Shi,Shuning Zheng,Robert Gerszten,C Ronald Kahn","doi":"10.1172/jci197556","DOIUrl":"https://doi.org/10.1172/jci197556","url":null,"abstract":"Glutathione (GSH) maintains a reduced cellular environment and is widely believed to mitigate disease-associated oxidative damage to proteins, thereby protecting against metabolic dysfunction-associated steatotic liver disease (MASLD). However, this widely accepted assumption remains largely untested because of challenges in physiologically manipulating hepatic GSH levels during disease development. Here, we have utilized liver-specific overexpression of cation transport regulator homolog 1 (Chac1), a recently identified intracellular GSH-degrading enzyme, to induce hepatic GSH depletion during MASLD progression. Contrary to canonical doctrine, GSH depletion unexpectedly protects against MASLD by substantially decreasing hepatic lipogenesis and fibrosis without triggering an oxidative stress response. Mechanistically, GSH depletion does not cause global protein oxidation but instead selectively oxidizes and destabilizes fatty acid synthase while decreasing lipogenic gene expression at the transcriptional level, collectively suppressing lipogenesis. Interestingly, Chac1 expression is decreased in livers of patients with MASLD, highlighting its potential therapeutic relevance. These findings revise the conventional view of GSH in protein redox and demonstrate that targeted redox manipulation through GSH depletion protects against MASLD.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"38 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147680439","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":"Therapy-induced cholesterol biosynthesis drives lung cancer dormancy and drug resistance.","authors":"Yikai Zhao,Yijia Zhou,Linnuo Pan,Geng G Tian,Hsin-Yi Huang,Shijie Tang,Ming Lu,Zhangsen Zhou,Peng Zhang,Luonan Chen,Lele Zhang,Liang Hu,Hongbin Ji","doi":"10.1172/jci191735","DOIUrl":"https://doi.org/10.1172/jci191735","url":null,"abstract":"Complete response is rarely observed in lung cancer molecular targeted therapy, despite great clinical success. Here, we found that molecular therapy targeted toward EGFR mutant, KRAS mutant, or ALK fusion lung cancer induced cholesterol biosynthesis, which promoted cancer cells to enter dormancy and thus escape drug killing. Combined statin treatments effectively blocked cholesterol biosynthesis, prevented cancer cells from entering dormancy, and thus resulted in dramatic tumor regression. We further identified a subpopulation of cycling cancer cells that persisted during molecular targeted therapy and remained sensitive to aurora kinase inhibitors. Triple-targeting cholesterol biosynthesis, aurora kinase, and individual oncogenic drivers almost eradicated all the cancer cells. Therapy-induced cancer dormancy was mainly attributed to activation of unfolded protein response, specifically the PERK-eIF2α axis, which triggers cholesterol biosynthesis and AKT signaling. Collectively, this work uncovers an unexpected role of a therapy-induced prosurvival program in promoting cancer dormancy and provides a potentially effective strategy to prevent drug resistance.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"128 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147680443","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":"Immune signaling and function in neurodegeneration.","authors":"Yvonne L Latour,Dorian B McGavern","doi":"10.1172/jci199850","DOIUrl":"https://doi.org/10.1172/jci199850","url":null,"abstract":"Neurodegenerative diseases arise from interactions among pathogenic proteins, immune responses, and diverse environmental or age-related stressors that disrupt CNS homeostasis. CNS resident microglia detect self-derived danger signals through pattern recognition receptors, and their activation can promote clearance of aberrant proteins, including amyloid-β, tau, α-synuclein, and TAR DNA-binding protein 43. However, microglial activation may also drive maladaptive states that amplify neuroinflammation. Microglial transitions are further shaped by receptor-mediated signaling and antigen presentation pathways that integrate environmental cues with functional responses. Adaptive immune cells contribute additional layers of regulation, with CD8+ and CD4+ T cells exerting neuroprotective or neurotoxic effects depending on disease context, activation state, and antigen specificity. The identification of granzyme K-expressing CD8+ T cells in several neurodegenerative conditions highlights the growing recognition that distinct T cell subsets may have specialized roles in disease. Aging, repetitive head injury, and viral infection further alter microglial phenotypes, weaken barrier integrity, promote T cell recruitment, and prime the CNS for chronic inflammation. In this review, we synthesize current knowledge of innate and adaptive immune mechanisms in neurodegeneration, examine how external factors influence these responses, and consider how these insights may guide future therapeutic strategies.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147680444","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":"Diet's rapid effects on the thyroid gland challenge unidirectional assumptions about hypothyroidism and energy balance.","authors":"Arturo Hernandez,Francesco S Celi","doi":"10.1172/jci205029","DOIUrl":"https://doi.org/10.1172/jci205029","url":null,"abstract":"Thyroid hormones provide crucial regulation of energy expenditure through their effects on thermogenesis, lipid metabolism, and mitochondrial function. Given their close relationship with overall metabolism, a deficit in thyroid hormones fittingly leads to a positive energy balance and weight gain. The direction of this process may also operate in reverse, according to recent research from Rampy et al. in this issue of JCI. These investigators found that mice introduced to a high-fat, high-sugar diet developed marked short-term intracellular stress and functional impairment in the thyroid gland, leading to alterations in serum thyroid hormone levels prior to measurable weight gain. This finding opens the possibility that thyroid dysfunction originates from persistent damage to the thyroid gland caused by sustained overnutrition.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"433 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147680441","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":"Unconscious uncoupling: dysfunctional neurovascular responses to low glucose in type 1 diabetes and impaired hypoglycemia awareness.","authors":"Stephanie A Amiel,Fernando O Zelaya","doi":"10.1172/jci205273","DOIUrl":"https://doi.org/10.1172/jci205273","url":null,"abstract":"Approximately 25% of individuals with type 1 diabetes (T1D) experience impaired awareness of hypoglycemia (IAH), a weakening of symptomatic neurohumoral responses to falling glucose levels that sharply increases risk of severe hypoglycemia. A recent study by Filip et al. used MRI-based arterial spin labeling to compare regional cerebral blood flow (CBF) responses to experimental hypoglycemia across 3 groups: individuals without T1D and individuals with T1D, with or without IAH. All groups showed a CBF response to hypoglycemia in brain regions involved in learning and interoception, among others, but the responses were qualitatively different between groups and blunted in the presence of IAH. The association between the regional CBF and the hormonal responses to hypoglycemia was inverted in IAH, compared with that in individuals with preserved awareness. The findings add to work linking changes in cognitive processing to IAH development and its persistence in some individuals.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147680404","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":"Gasdermin E: a missing link in muscle regeneration.","authors":"Swathy Krishna,Jill A Rafael-Fortney","doi":"10.1172/jci205442","DOIUrl":"https://doi.org/10.1172/jci205442","url":null,"abstract":"Skeletal muscle has the impressive capacity to completely regenerate even after relatively severe injuries in young individuals, but this process is dysregulated in multiple cell types in the microenvironment in numerous diseases and aging. In this issue of the JCI, Cao et al., using an elegant set of genetic mouse models and pharmacological approaches, demonstrated that gasdermin E (GSDME) was required in myeloid cells after sterile muscle injury to normally regenerate muscle and that downstream IL-18 release prevented intramuscular ectopic fat deposition. GSDME expression was reduced in human muscles from aged individuals, and Gsdme was increased after muscle injury in young, but not old, mice. The ability of IL-18 to partially improve regeneration in aged GSDME-knockout mice demonstrates the potential clinical relevance of this finding in dysregulated muscle regeneration associated with aging.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147680440","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}