JCI insight最新文献

{"title":"Vorinostat for graft-versus-host disease prevention in pediatric and young adult patients with hematologic malignancies.","authors":"Nicolas Parnell, Xiao Cao, Jan H Beumer, Thomas M Braun, Yilei Cui, Gary J Fisher, Guoqing Hou, Julianne Holleran, Tracey Churay, Michelle Rozwadowski, Luna Heider, Mark T Vander Lugt, Carrie L Kitko, April L Rahrig, Ed Peres, Kirsten M Williams, Julie-An Talano, Vanessa A Fabrizio, Ghada Abusin, Gregory A Yanik, John Magenau, Mary Riwes, Marcus J Geer, Sarah Anand, Monalisa Ghosh, Attaphol Pawarode, Kristen Votruba, Pavan Reddy, Sung Won Choi","doi":"10.1172/jci.insight.210272","DOIUrl":"https://doi.org/10.1172/jci.insight.210272","url":null,"abstract":"<p><strong>Background: </strong>This prospective, single-arm, multicenter phase 1/2 trial evaluated vorinostat added to standard graft-versus-host disease (GVHD) prophylaxis in pediatric, adolescent, and young adult (AYA) patients undergoing allogeneic hematopoietic cell transplantation (HCT) from HLA-matched related, HLA-matched unrelated, and haploidentical donors.</p><p><strong>Methods: </strong>Patients aged 3-39 years received twice-daily vorinostat with tacrolimus/methotrexate after HLA-matched HCT from day -10 to +30, or with post-transplant cyclophosphamide/tacrolimus/mycophenolate mofetil after haploidentical HCT from day +5 to +30. The primary endpoint was cumulative incidence of grade II-IV acute GVHD by day +100. All outcomes were based on intention-to-treat analysis.</p><p><strong>Results: </strong>Forty-three patients were enrolled; median age was 19 years, with 74% receiving HLA-matched and 26% haploidentical HCT. The recommended phase 2 dose was 60 mg/m² twice daily. No dose-limiting toxicities, unexpected vorinostat-related serious adverse events, or primary graft failures occurred. Median neutrophil and platelet recovery occurred at 14 and 18 days, respectively. Day +100 grade II-IV and III-IV acute GVHD were 14% (95% CI, 5.6, 26) and 4.7% (95% CI, 0.83, 14), respectively. One-year overall survival was 88.4% (95% CI, 79.3, 98.5), relapse 14% (95% CI: 5.6, 26), nonrelapse mortality 4.7% (95% CI: 0.8, 14), and GVHD-free/relapse-free survival 55.8% (95% CI: 42.8, 72.8). Correlative studies demonstrated on-target HDAC activity, with increased histone acetylation and lower proinflammatory cytokines.</p><p><strong>Conclusion: </strong>These findings support randomized evaluation of vorinostat-based GVHD prophylaxis in pediatric and AYA HCT.</p><p><strong>Trial registry: </strong></p><p><strong>Clinicaltrials: </strong>gov, NCT03842696.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038828","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":"Long-term reprogramming of classical monocytes with altered ontogeny mediates enhanced lung injury in sepsis survivors.","authors":"Scott J Denstaedt, Breanna McBean, Alan P Boyle, Brett C Arenberg, Matthias Mack, Bethany B Moore, Michael W Newstead, Yamei Deng, Alexey I Nesvizhskii, Benjamin H Singer, Jennifer Cano, Hallie C Prescott, Helen S Goodridge, Rachel L Zemans","doi":"10.1172/jci.insight.198551","DOIUrl":"10.1172/jci.insight.198551","url":null,"abstract":"<p><p>Patients who survive sepsis are predisposed to new hospitalizations for respiratory failure, but the underlying mechanisms are unknown. Using a murine model in which prior sepsis predisposes to enhanced lung injury, we previously discovered that classical monocytes persist in the lungs after long-term recovery from sepsis and exhibit enhanced cytokine expression after secondary challenge with intra-nasal lipopolysaccharide. Here, we hypothesized that immune reprogramming of post-sepsis monocytes and altered ontogeny predispose to enhanced lung injury. Monocyte depletion and/or adoptive transfer was performed three weeks and three months after sepsis. Monocytes from post-sepsis mice were necessary and sufficient for enhanced LPS-induced lung injury and promoted neutrophil degranulation. Prior sepsis enhanced JAK-STAT signaling and AP-1 accessibility in monocytes and shifted monocytes toward the neutrophil-like monocyte lineage. Neutrophil-like monocytes demonstrated a pro-inflammatory phenotype with enhanced IL-1β expression and reduced phagocytic capacity. In human sepsis and/or pneumonia survivors, monocytes were predictive of 90-day mortality and exhibit transcriptional and proteomic neutrophil-like signatures. We conclude that sepsis reprograms monocytes into a pro-inflammatory phenotype and skews bone marrow progenitors and monocytes toward the neutrophil-like lineage, predisposing them to induce neutrophil degranulation and lung injury.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038766","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":"SIV infection disrupts the spatial cellular and communication networks of pulmonary granulomas during SIV/MTB co-infection.","authors":"Jessica M Medrano, Persis Sunny, Collin R Diedrich, Pauline Maiello, Christopher Kline, Tara Rutledge, Edwin Klein, Joshua T Mattila, Jishnu Das, Zandrea Ambrose, Philana Ling Lin","doi":"10.1172/jci.insight.208488","DOIUrl":"10.1172/jci.insight.208488","url":null,"abstract":"<p><p>Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is the leading infectious cause of death globally. Despite wide use of antiretroviral therapy (ART) by people living with HIV, the risk of TB remains increased. To understand immune interactions within lung granulomas, we compared spatial transcriptomics of Mtb and simian immunodeficiency virus (SIV) in co-infected macaques with or without ART as a model for HIV/Mtb co-infection. Spatially differentiated transcriptional profiles were observed in Mtb-only granulomas, with myeloid cells enriched in metabolic/antimicrobial pathways within the inner ring and T cell co-stimulatory/activation pathways enriched in the outer ring. These spatially distinct patterns were lost in SIV/Mtb granulomas with higher enrichment in type I IFN pathways compared to Mtb-only granulomas. SIV/ART/Mtb granulomas had an intermediate transcriptional pattern without restoration to Mtb-only granulomas, despite a lack of viral replication. Cell-cell communication was reduced among SIV/Mtb co-infected groups. These data suggest that HIV disrupts spatially organized immune functions of granulomas, which are not fully restored by ART.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038750","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":"T-cell responses shape infant SIV reservoirs and post-intervention control following AAV9-eCD4-Ig and latency reversal.","authors":"Jairo A Fonseca, Alexis C King, Kaleaha S Davis, Daniel O'Hagan, Adrian Khoei, Lucas Alves Britto Da Costa, Camryn Cockerham, Mackenzie Cottrell, Stephanie Ehnert, Jennifer S Wood, Michael D Alpert, Matthew R Gardner, Jeffrey D Lifson, Maud Mavigner, Mauricio A Martins, Ann Chahroudi","doi":"10.1172/jci.insight.208375","DOIUrl":"10.1172/jci.insight.208375","url":null,"abstract":"<p><p>Early antiretroviral therapy (ART) limits viral reservoir establishment in infants but also constrains viral-specific immunity required to clear reactivated cells. In the early ART context, we evaluated whether combining adeno-associated virus serotype 9 (AAV9)-vectored eCD4-IgG1 with pharmacologic latency reversal using the second mitochondria-derived activator of caspases (SMAC) mimetic AZD5582 could promote reservoir reduction and control in simian immunodeficiency virus (SIV)-infected infant macaques. AAV9 delivery achieved sustained eCD4-IgG1 expression and AZD5582 induced on-ART viremia, but the combination did not reduce intact SIV proviral DNA relative to controls. Partial post-intervention control of viremia during Analytical Treatment Interruption (ATI) occurred in 2/6 infants receiving AAV9-eCD4-IgG1 + AZD5582 with restricted reservoir expansion during recrudescence at week 13. Intact reservoir size during ATI correlated inversely with on-ART viremia during AZD5582 treatment. Controllers did not show increased eCD4-IgG1 expression nor increased on-ART viremia during AZD5582 treatment, but harbored less pre-ART intact SIV DNA in PBMCs than non-controllers. Controllers also exhibited higher frequencies and greater polyfunctionality of virus-specific CD8+ T-cells prior to ATI. These findings implicate immune control of reservoir size and post-ART viral dynamics in early-treated infants and suggest that AAV9-eCD4-IgG1 + AZD5582 increases the likelihood of post-ART viral control.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038838","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":"Loss of ADAMTS9 disrupts ciliogenesis and collagen homeostasis resulting in Nephronophthisis-like polycystic kidneys.","authors":"Sydney Fischer, Karyn L Robert, Manu Ahmed, Griffin I Kane, Matthew A Kavanaugh, Wei Wang, Pamela V Tran, Prabhani U Atukorale, Sumeda Nandadasa","doi":"10.1172/jci.insight.203950","DOIUrl":"10.1172/jci.insight.203950","url":null,"abstract":"<p><p>ADAMTS9 mutations cause the ciliopathies nephronophthisis and Joubert syndrome. Here we demonstrated that deletion of ADAMTS9 in the proximal nephron led to polycystic kidney development in mice. In males, Adamts9 deletion caused kidneys to become highly cystic while remaining small without undergoing enlargement. In contrast, female mice developed cystic kidneys at a slower rate. ADAMTS9 deletion disrupted ciliogenesis through the loss of cleavage of the ciliary transition zone (TZ) protein TMEM67, which led to loss of the MKS/B9 module - a key component of the ciliary gate. Functional analysis of all eight ciliopathy patient variants of ADAMTS9 identified to date showed TMEM67 C-terminus failed to localize to the TZ, thus disrupting a key regulatory mechanism in patient renal ciliogenesis. Modeling ADAMTS9-mediated TMEM67 cleavage utilizing TMEM67-cleavage deficient mice revealed loss of TZ formation, but not elevated canonical Wnt signaling as the underlying mechanism driving cystogenesis. Adamts9 deletion led to comparatively intense interstitial collagen deposition, which likely restricted kidney enlargement and resulted in the characteristically small kidney phenotype seen in nephronophthisis. By comparative analysis of four interconnected polycystic kidney models, in addition to Pkd1 and Pkd2 deleted kidneys, we identified differential collagen homeostasis as a principle factor determining cystic kidney size and type.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038747","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":"Mild caloric restriction accelerates atherosclerosis via dysregulated cholesterol homeostasis and lipogenesis in HCHF-fed ApoE-deficient mice.","authors":"Yun Zhu, Yanzhe Xu, Gerhard Liebisch, Juergen Borlak","doi":"10.1172/jci.insight.202798","DOIUrl":"https://doi.org/10.1172/jci.insight.202798","url":null,"abstract":"<p><p>Recent ACC/AHA guidelines recommend ≥5% weight loss over six months to reduce cardiovascular risk in obesity. However, some populations paradoxically exhibit increased cardiovascular disease (CVD) following weight loss. We investigated whether mild food restriction (MfR) accelerates atherogenesis through pro-atherogenic lipid remodelling. ApoE-deficient mice were fed Chow or a high-cholesterol/high-fat(HCHF) diet for six months, with MfR producing 5% lower body-weight gain. Atherosclerotic burden was quantified histologically, and hepatic lipidomes were analysed by ESI-MS/MS and compared with plasma lipidomic profiles from CVD patients. MfR improved insulin sensitivity by lowering blood glucose and triglycerides but increased circulating cholesterol and accelerated atherosclerosis. HCHF-fed mice developed larger, more numerous plaques with increased necrotic core formation, thinner fibrous caps, higher intima-to-media ratios, and inflammatory cell infiltration. Similar pro-atherogenic changes occurred in Chow-fed mice subjected to MfR. Mechanistically, MfR increased hepatic free cholesterol and enriched pro-atherogenic phosphatidylcholine, phosphatidylethanolamine, lysophosphatidylcholine, sphingomyelin, ceramide, and cholesterol ester species, yielding a CERT1 score of 8.1 indicative of cardiovascular risk. These lipid alterations mirrored plasma lipidomic signatures from CVD patients with diabetes. Collectively, our findings demonstrate that mild caloric restriction is not universally atheroprotective and can accelerate atherosclerosis in hypercholesterolaemic states by disrupting cholesterol homeostasis and promoting pro-atherogenic lipid remodelling.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074359","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":"Urine leukemia inhibitory factor predicts kidney function recovery in patients with acute interstitial nephritis.","authors":"Long Qian, Megan L Baker, Laura Aponte Becerra, Cathleen Liang, Emma Koval, Kyra Shelton, Daris Javed, Gilbert Moeckel, Deepika Kumar, Avi Z Rosenberg, Michael Kuperman, Tinyi Chu, Wassim Obeid, Xuefei Tian, Chirag R Parikh, Leyuan Xu, Jonathan Barasch, Shuta Ishibe, Lloyd G Cantley, Dennis G Moledina","doi":"10.1172/jci.insight.200389","DOIUrl":"10.1172/jci.insight.200389","url":null,"abstract":"<p><p>A urine protein called LIF predicts kidney recovery after a common kidney injury called acute interstitial nephritis, potentially guiding treatment decisions and prognosis.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 18","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13596714/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016738","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":"Neutrophils promote endothelial cell activation in pediatric Mycoplasma pneumoniae pneumonia.","authors":"Xia Huang, Yifan Zhu, Yun Guo, Tian Lv, Haiyan Gu, Yingying Luo, Dan Li, Hang Sun, Deyu Zhao, Feng Liu","doi":"10.1172/jci.insight.203856","DOIUrl":"10.1172/jci.insight.203856","url":null,"abstract":"<p><p>Mycoplasma pneumoniae pneumonia (MPP) can cause serious extrapulmonary complications, including life-threatening thrombosis. This study aimed to elucidate the roles of neutrophils and neutrophil extracellular traps (NETs) in vascular endothelial cell (EC) activation in pediatric MPP-associated thrombosis. We analyzed the relationship between neutrophils and thrombosis in children with MPP and used mouse models of neutrophilia (Csf3 plasmid injection), neutropenia (Csf3 deficient, Csf3-/-), and defective NETs formation (Pad4 deficient, Pad4-/-). The effects of neutrophils and NETs on EC activation were further examined in vivo, in vitro, and in human samples. Elevated neutrophil count was observed in patients with thrombosis and functioned as a potential diagnostic marker as well as a risk factor for MPP-associated thrombosis. EC activation was enhanced in MPP mice with neutrophilia but attenuated in neutropenic or Pad4-/- mice. NETs activated ECs through TLR2 and JAK/STAT3 signaling, and inhibition of NETs formation (Cl-amidine), TLR2 (C29), and JAK (upadacitinib) each attenuated this response. Strong correlations among neutrophils, NETs, EC activation, and thrombosis were observed in pediatric patients. These findings suggest that neutrophils promoted thrombosis in MPP via NETs-mediated EC activation involving TLR2 and JAK/STAT3 signaling. This study provides mechanistic insights into the inflammatory-thrombotic processes in MPP-associated thrombosis and offers a rationale for further investigation of neutrophils, NETs, TLR2, and JAK/STAT3 signaling in this context.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 18","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13596722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016747","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":"Right ventricular pressure overload disturbs T-tubule maturation via MEF2D's transcriptional regulation of BIN1.","authors":"Yuqing Hu, Yiting Xue, Xudong Chen, Linghui Kong, Debao Li, Zheng Wang, Sixie Zheng, Siqi She, Hao Li, Sijuan Sun, Hao Chen, Lijun Chen, Peisen Ruan, Kai Wang, Lincai Ye","doi":"10.1172/jci.insight.204032","DOIUrl":"10.1172/jci.insight.204032","url":null,"abstract":"<p><p>Right ventricular pressure overload (RVPO) is a critical pathophysiological feature of numerous pediatric cardiovascular diseases. Transverse tubules (T-tubules) form the foundation for efficient excitation-contraction coupling in mature cardiomyocytes. We hypothesized that RVPO impairs T-tubule maturation through the regulatory protein bridging integrator 1 (BIN1). In right ventricular samples from children with tetralogy of Fallot, characterized by RVPO, and in a neonatal rat RVPO model induced by pulmonary artery banding (PAB), T-tubule maturation was disrupted. RNA-seq revealed significant downregulation of T-tubule-associated genes, with Bin1 among the most suppressed. Bin1 overexpression restored T-tubule maturation in PAB rats. ATAC-seq showed reduced chromatin accessibility at Bin1 loci; motif analysis identified Mef2d (myocyte enhancer factor 2D) as the top enriched transcription factor. Mef2d knockdown rescued Bin1 expression and T-tubule maturation, and mutation of the Mef2d binding sites within the Bin1 promoter abolished the inhibitory effect of Mef2d on Bin1 promoter activity. This study delineates a phenomenon and a mechanism of cardiomyocyte maturation under pathological stress. The findings not only advance our understanding of this most pivotal event in postnatal cardiac development but also unveil a potential therapeutic direction for pediatric cardiovascular diseases associated with RVPO.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 18","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13596720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016815","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":"Integrated single-cell multiomics reveals neutrophil-driven immune-metabolic reprogramming of Kupffer cells via thrombospondin-1/CD36 after surgical stress.","authors":"Hongji Zhang, Xingping Huang, Preethi Jayakumar, Yunwei Zhang, Ti Yang, Xiaorong Guo, Grace Wu, Amrendra Kumar, Vijaya Bharti, Amblessed Onuma, Chengli Shen, Dequan Lou, Patricia S Latham, James M Crawford, Kong Chen, Anna E Vilgelm, Lopa Mishra, Allan Tsung, Meihong Deng, Hai Huang","doi":"10.1172/jci.insight.203495","DOIUrl":"10.1172/jci.insight.203495","url":null,"abstract":"<p><p>Surgical stress, such as liver ischemia/reperfusion (I/R) injury characterized by robust neutrophil infiltration and immune activation, induces sterile inflammation that reshapes tissue immunity and contributes to organ dysfunction, yet the intercellular circuits that spatially orchestrate these responses within the hepatic immune microenvironment remain incompletely defined. Here, we integrate single-cell RNA sequencing, spatial transcriptomics, high-dimensional spectral flow cytometry, and metabolomics to resolve the hepatic immune landscape following I/R at cellular and spatial resolution. While confirming extensive immune remodeling, we identify a dominant neutrophil-Kupffer cell communication axis mediated by neutrophil-derived thrombospondin-1 (TSP-1), which selectively engages CD36 on Kupffer cells. This interaction drives coordinated immune-metabolic reprogramming in Kupffer cells, characterized by suppression of oxidative phosphorylation, enhanced glycolysis, and remodeling of sphingolipid metabolism, including accumulation of hexosylceramides. Spatial analyses reveal preferential neutrophil-Kupffer cell colocalization within necrotic niches, and cross-species integration with human liver transplant datasets demonstrates conserved upregulation of the TSP-1/CD36 axis following reperfusion. Pharmacologic inhibition of TSP-1 attenuates liver injury and inflammatory responses in vivo. Together, these findings define a spatially organized, neutrophil-driven immune-metabolic circuit that governs functional reprogramming of Kupffer cells during surgical stress and identify the TSP-1/CD36 pathway as a conserved and targetable mediator of sterile liver injury.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 18","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13596724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016741","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}