Biochimica et biophysica acta. Molecular basis of disease最新文献

{"title":"TANK-binding kinase 1 inhibitor GSK8612 suppresses platelet function and thrombosis via the ERK/P38 signaling pathway","authors":"Chengying Gu ,&nbsp;Liang Wang ,&nbsp;Ran Tian ,&nbsp;Hao Qian ,&nbsp;Ming Wu ,&nbsp;Xueqing Zhu ,&nbsp;Sainan Li ,&nbsp;Wei Zuo ,&nbsp;Zhenyu Liu ,&nbsp;Shuyang Zhang","doi":"10.1016/j.bbadis.2025.168101","DOIUrl":"10.1016/j.bbadis.2025.168101","url":null,"abstract":"<div><h3>Introduction</h3><div>TANK-binding kinase 1 (TBK1) is a protein kinase that contributes to cell signaling and regulates immune responses, apoptosis, and inflammatory processes. However, the role of TBK1 in platelets is unknown. In this study, GSK8612, a TBK1 inhibitor, was used to investigate the connection between TBK1 and collagen- or thrombin-stimulated platelets.</div></div><div><h3>Methods</h3><div>Immunoblot analysis, platelet aggregation, granule release, flow cytometry, adhesion assay, clot retraction, assessment of reactive oxygen species (ROS), evaluation of rat tail bleeding time, rat carotid artery and vein thrombosis model were performed.</div></div><div><h3>Results</h3><div>This study revealed elevated levels of phosphorylated TBK1 (p-TBK1) in patients with acute myocardial infarction compared to healthy controls. Furthermore, <em>in vitro</em> experiments demonstrated rapid TBK1 phosphorylation upon platelet stimulation. GSK8612, a specific TBK1 inhibitor, suppressed platelet aggregation, granule secretion, adhesion, and clot retraction. GSK8612 prolonged rat tail bleeding time and inhibited both the arterial and vein thrombotic process. However, it did not affect platelet counts, coagulation, or key receptor expression such as glycoprotein (GP) VI, GPIbα, and integrin αIIbβ3. Correspondingly, GSK8612 significantly attenuated ROS generation in activated platelets. It significantly suppressed the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38 MAPK), indicating that TBK1 inhibition disrupts redox balance and downregulates MAPK-mediated pro-thrombotic signaling.</div></div><div><h3>Conclusions</h3><div>Pharmacological inhibition of TBK1 impaired platelet function and thrombus formation, an effect that may be attributed to the suppression of ROS generation <em>via</em> the ERK/P38 signaling axis. This finding suggests that TBK1 may be a new target for treating thrombotic or cardiovascular occlusion diseases.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 2","pages":"Article 168101"},"PeriodicalIF":4.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145433394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “High fluid shear stress induces Hippo/YAP pathway in articular cartilage superficial layer cells: a potential mechanistic link to osteoarthritis” [BBA – Mol. Basis Dis. (May 29 2025) 167939]","authors":"Haitao Li ,&nbsp;Yuxuan Ou ,&nbsp;Lifu Chen ,&nbsp;Hongtao Tian ,&nbsp;Jian Wang ,&nbsp;Wei Tong","doi":"10.1016/j.bbadis.2025.168086","DOIUrl":"10.1016/j.bbadis.2025.168086","url":null,"abstract":"","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 2","pages":"Article 168086"},"PeriodicalIF":4.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145357188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of TLR4-NF-κB signaling in renal tubular epithelial cells facilitates renal allograft fibrosis by inhibiting peroxisome biogenesis","authors":"Dan Zhang ,&nbsp;Yang-He Zhang ,&nbsp;Bin Liu ,&nbsp;Hong-Xia Yang ,&nbsp;Guang-Tao Li ,&nbsp;Hong-Lan Zhou ,&nbsp;Yi-Shu Wang ,&nbsp;Zhi-Xiang Xu","doi":"10.1016/j.bbadis.2025.168066","DOIUrl":"10.1016/j.bbadis.2025.168066","url":null,"abstract":"<div><div>Interstitial fibrosis is a key factor affecting the long-term survival of renal allografts. The Toll-like receptor 4 (TLR4)-nuclear factor kappa B (NF-κB) signaling pathway is widely activated in renal allografts, inducing inflammation and playing a pivotal role in the progression of fibrosis. However, it remains unclear whether NF-κB activation promotes renal allograft fibrosis through non-inflammatory mechanisms. In this study, we identified a negative correlation between NF-κB expression and peroxisomal biogenesis factor 5 (PEX5). In both rat renal allograft models and human kidney-2 (HK−2) cells, TLR4/NF-κB signaling suppressed <em>PEX5</em> expression, leading to impaired peroxisome biogenesis and dysfunction. Mechanistically, TLR4/NF-κB signaling downregulated <em>PEX5</em> expression by upregulating DNA methyltransferase 1 (DNMT1), and pharmacological inhibition of NF-κB or DNMT1 restored <em>PEX5</em> levels. Peroxisomal dysfunction promoted epithelial-to-mesenchymal transition (EMT) and impaired the ability of peroxisomes to clear hydrogen peroxide, thereby accelerating fibrosis progression. Notably, pharmacological inhibition of DNMT1 effectively delayed the progression of fibrosis in renal allografts. In conclusion, these findings demonstrate that the NF-κB/DNMT1/PEX5 signaling pathway suppresses peroxisome biogenesis in renal allografts, and the amelioration of allograft fibrosis by pharmacologic DNMT1 inhibition underscores the translational relevance of this pathway. Targeting this pathway may provide a potential therapeutic strategy to improve renal allograft survival.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 2","pages":"Article 168066"},"PeriodicalIF":4.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145289588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced cargo of plasma alpha B crystallin in oligodendrocyte-derived exosomes accompanied by elevated expression of inflammatory factors in the temporal cortex of patients with refractory epilepsy","authors":"Xiaoshuai Ji ,&nbsp;Dongyan Wu ,&nbsp;Yongsheng Xie ,&nbsp;Ming Chen ,&nbsp;Zengxin Qi ,&nbsp;Nan Zhou","doi":"10.1016/j.bbadis.2025.168096","DOIUrl":"10.1016/j.bbadis.2025.168096","url":null,"abstract":"<div><h3>Purpose</h3><div>Plasma exosomes have emerged as key mediators of communication between neural cells and the periphery, playing pivotal roles in various neurological diseases. However, their involvement in the pathogenesis of epilepsy remains unclear. This study aimed to investigate the expression of alpha B crystallin (CRYAB) in plasma exosomes and the temporal cortex as a potential contributor to epileptogenesis.</div></div><div><h3>Methods</h3><div>The study included 112 participants, comprising patients with refractory medial temporal lobe epilepsy, glioma patients with and without pre-operative epilepsy, and age- and sex-matched healthy controls. Plasma exosomes were isolated from peripheral blood using immuno-co-precipitation and resin antibody techniques. Exosome morphology and size distribution were evaluated using transmission electron microscopy and nanoparticle tracking analysis. Neuron- or glia-derived exosomes were enriched through antibody-based immunoabsorption. Plasma CRYAB levels were quantified using an enzyme-linked immunosorbent assay. CRYAB expression in neurons and glia of the human temporal cortex was evaluated by immunocytochemistry. Western blotting was performed to detect the expression levels of CRYAB and inflammatory cytokines in brain tissue.</div></div><div><h3>Results</h3><div>Isolated circulating exosomes were confirmed to be partially derived from the central nervous system (CNS), as evidenced by the presence of neuronal and glial markers. CRYAB was highly expressed in exosomes derived from oligodendrocytes. Patients with epilepsy exhibited significantly elevated levels of plasma oligodendrocyte-derived exosomal CRYAB compared to healthy controls. This was paralleled by increased expression of CRYAB in the temporal cortex of patients with epilepsy, indicating CNS origin of the exosomal cargo. A negative correlation between plasma CRYAB levels and oligodendrocyte-derived exosomal CRYAB was observed in both controls and epileptic patients. Furthermore, patients with epilepsy demonstrated significantly higher density of CRYAB immunoreactivity in temporal cortex oligodendrocytes. The temporal cortex of patients with refractory epilepsy exhibited a significant upregulation of CRYAB, concomitant with elevated levels of inflammatory cytokines.</div></div><div><h3>Conclusion</h3><div>The finding that plasma oligodendrocyte-derived exosomal CRYAB is upregulated in patients with epilepsy highlights a potential role of oligodendrocyte-secreted CRYAB in its pathogenesis.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 2","pages":"Article 168096"},"PeriodicalIF":4.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145413782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"M1 macrophages enhance breast cancer chemoresistance via JAK-STAT3 signaling","authors":"Yining Feng ,&nbsp;Fei Chen ,&nbsp;Chenglong Mu ,&nbsp;Luqi Wang ,&nbsp;Yuhan Jiang ,&nbsp;Dan Liu ,&nbsp;Dameng Li ,&nbsp;Chen Liang ,&nbsp;Yanhua Zhai ,&nbsp;Tao Yang ,&nbsp;Alan Wells ,&nbsp;Amanda M. Clark ,&nbsp;Liang Wei ,&nbsp;Bo Ma","doi":"10.1016/j.bbadis.2025.168056","DOIUrl":"10.1016/j.bbadis.2025.168056","url":null,"abstract":"<div><div>Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment, playing a key role in breast cancer (BrCa) progression and chemotherapy response. While TAMs exhibit diverse phenotypes, the M1/M2 classification remains widely used. M1-like macrophages are known for tumor-killing properties, whereas M2-like macrophages promote tumor growth. However, the impact of TAM subtypes on chemotherapy response remains inconsistent. In this study, we found that M1-like macrophages or their conditioned medium (CM) induced greater BrCa cell death and inhibited proliferation compared to M2-like macrophages. Surprisingly, BrCa cells surviving M1-like macrophage-induced killing displayed increased chemotherapy resistance, independent of proliferation. Transcriptomic profiling indicated upregulation of the JAK–STAT signaling pathway, with elevated STAT3 phosphorylation subsequently confirmed at the protein level. Inhibition of JAKs with Ruxolitinib reduced STAT3 activation and restored chemotherapy sensitivity. Our findings highlight the dual role of M1-like macrophages, demonstrating both tumoricidal activity and the potential to induce chemotherapy resistance in surviving tumor cells, offering insights for macrophage-targeted therapies.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 1","pages":"Article 168056"},"PeriodicalIF":4.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Piezo1 promotes M1 macrophage polarization and impairs osteogenic differentiation in bone infection","authors":"Rong-Shen Yang ,&nbsp;Shuan-Ji Ou ,&nbsp;Wei Zeng ,&nbsp;Yu-Dun Qu ,&nbsp;Jia-Xuan Li ,&nbsp;Jiang-Ping Wen ,&nbsp;Jia-Bao Liu ,&nbsp;Chang-Liang Xia ,&nbsp;Yong Qi ,&nbsp;Chang-Peng Xu","doi":"10.1016/j.bbadis.2025.168042","DOIUrl":"10.1016/j.bbadis.2025.168042","url":null,"abstract":"<div><h3>Background</h3><div>Bone infection induces a strong inflammatory response and leads to impaired bone regeneration, in which macrophages sense mechanistic signals and modulate immune responses in the inflammatory microenvironment through Piezo1. Nonetheless, the regulatory role of Piezo1 in macrophages during bone infection remains elusive.</div></div><div><h3>Methods</h3><div>Rat models of infected bone defects were established for bulk RNA sequencing and single-cell RNA sequencing. Tissues were collected from infected human bones and infected bone marrow cavity tissues of rats for in vivo validation. Indirect co-culture cell experiments were conducted using mouse mononuclear macrophages and mouse bone marrow mesenchymal stem cells for <em>in virto</em> validation.</div></div><div><h3>Results</h3><div>Piezo1 was upregulated in bone marrow macrophages during infection, driving M1 polarization and inflammatory cytokine secretion, which triggered PANoptosis and impaired the osteogenic differentiation of bone marrow mesenchymal stem cells. Piezo1 inhibition attenuated these effects, confirming its regulatory role.</div></div><div><h3>Conclusions</h3><div>Within the inflammatory microenvironment during infection, Piezo1 expression is increased in macrophages and mediates macrophage polarization toward M1 and pro-inflammatory cytokine secretion, inducing PANoptosis and impairing osteogenic differentiation in bone marrow mesenchymal stem cells. Targeting Piezo1-mediated crosstalk between macrophages and bone marrow mesenchymal stem cells offers a novel strategy for restoring bone regeneration in bone infection.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 1","pages":"Article 168042"},"PeriodicalIF":4.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging roles of heme oxygenase 2 (HO-2) in cancer: Implications for diagnosis and therapy","authors":"Sonny C. Ramos ,&nbsp;Seung-Hyun Jeong ,&nbsp;Yong-An Lee ,&nbsp;Jong-Jin Kim","doi":"10.1016/j.bbadis.2025.168057","DOIUrl":"10.1016/j.bbadis.2025.168057","url":null,"abstract":"<div><div>Heme oxygenases (HOs) are critical enzymes that regulate cellular redox balance, immune signaling, and iron metabolism through the degradation of heme into biliverdin, carbon monoxide (CO), and ferrous iron (Fe²⁺). While HO-1, the inducible isoform, has been extensively studied for its roles in tumor progression, inflammation, and therapy resistance, HO-2, the constitutively expressed isoform, has historically received limited attention. However, emerging evidence suggests that HO-2 contributes to cancer pathogenesis through mechanisms distinct from HO-1, including the regulation of tumor-initiating cells, angiogenesis, oxidative stress responses, and immune modulation. These findings position HO-2 as an underexplored yet promising target for cancer diagnosis and therapy. In this review, we summarize the structural and functional differences between HO-1 and HO-2, examine the emerging roles of HO-2 in various malignancies, and discuss its potential as a diagnostic biomarker and therapeutic target. We also highlight recent advances in selective chemical tools that enable the visualization and functional inhibition of HO-2 in cancer models.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 1","pages":"Article 168057"},"PeriodicalIF":4.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is tau pathology a relevant factor in neuronal damage induced by alcohol and other drugs?","authors":"Margrethe A. Olesen ,&nbsp;Andrés Ancía ,&nbsp;Rodrigo A. Quintanilla","doi":"10.1016/j.bbadis.2025.168059","DOIUrl":"10.1016/j.bbadis.2025.168059","url":null,"abstract":"<div><div>Unrestricted alcohol consumption and other substances like methamphetamine (ecstasy), opioids, cannabis, and cocaine have generated serious health concerns in the world population. The abusive use of these substances produces neuropathological alterations that could lead to cognitive decline and neurodegeneration. Pathological damage generated by these drugs resembles neurodegenerative changes observed in neurological disorders (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and others. One of the relevant elements distinguished in these diseases is the aggregation of intraneuronal proteins and deregulation of the neuronal cytoskeleton. In this context, the toxic modification of tau protein, a microtubule-associated protein (MAP), has raised new interest in drug and alcohol abuse research. Tau can undergo different pathological changes in which its anomalous phosphorylation and truncation state are relevant for NDs. These modifications produce a detachment from microtubule structures, affecting axonal transport and synaptic plasticity.</div><div>Current studies suggest that alcohol and drug abuse may affect the mechanisms behind tau phosphorylation, inducing dysregulation of kinase/phosphatase activities and toxic tau accumulation. These alterations could be a key element that contributes to cognitive decline and neurodegeneration caused by substance abuse.</div><div>Therefore, it is pivotal to understand how alcohol and other drugs contribute to neuronal damage by inducing tau pathology. This knowledge could generate new strategies and biomedical targets to reduce addictive consumption, neurodegeneration, and cognitive decline produced by substance abuse.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 1","pages":"Article 168059"},"PeriodicalIF":4.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145119301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Palmitic acid induces macrophage sialylation via TLR4/MyD88/TRAF6/NF-κB signaling","authors":"Niting Wu ,&nbsp;Pengbo Wang ,&nbsp;Xiaodong Ran ,&nbsp;Lin Li ,&nbsp;Yuanting She ,&nbsp;Jiawei Wang ,&nbsp;Dongfeng Zeng ,&nbsp;Xiaohui Li ,&nbsp;Yi Jia ,&nbsp;Yan Huang","doi":"10.1016/j.bbadis.2025.168064","DOIUrl":"10.1016/j.bbadis.2025.168064","url":null,"abstract":"<div><h3>Objective</h3><div>Globalization has spread Western diets and lifestyles beyond traditional boundaries. These patterns increase the risk of metabolic disorders and promote low-grade inflammation. However, the role of macrophage glycosylation in this context is still not fully elucidated. In this study, we examined the impact of PA-induced macrophage inflammation on cellular sialylation and its functional consequences.</div></div><div><h3>Approach and results</h3><div>In vitro, immunofluorescence, flow cytometry, and Western blot analyses showed that TLR4/MyD88/TRAF6/NF-κB signaling activation promotes macrophage polarization 24 h after PA treatment. Metabolomics, Neu5Ac tracing, immunofluorescence, transwell assays, and Western blot demonstrated that PA upregulates Cytidine monophosphate <em>N</em>-acetylneuraminic acid synthetase (CMAS) and ST3 beta-galactoside alpha-2, 3-sialyltransferase III (ST3Gal-III) expression, promoting CMP-Neu5Ac and Neu5Ac metabolism, macrophage sialylation, and migration. TLR4-in-C34 blockade reversed these effects. In vivo, blood biochemical analysis, ELISA, flow cytometry, and liver tissue sectioning showed that a high-fat diet increases serum and hepatic lipid levels, promotes sialylation, and increases peritoneal and hepatic macrophage numbers. Immunofluorescence, flow cytometry, and Western blot confirmed that a high-fat diet activates TLR4 signaling in macrophages, driving M1 polarization and CMAS/ST3Gal-III upregulation.</div></div><div><h3>Conclusion</h3><div>A high-fat diet increases PA levels and activates the TLR4/MyD88/TRAF6/NF-κB signaling pathway in macrophages, thereby upregulating CMAS and ST3Gal-III expression. Thus, it not only induces the M1 polarization of macrophages, thereby augmenting the inflammatory response, but also modulates sialylation, facilitating the recruitment of macrophages to tissues.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 1","pages":"Article 168064"},"PeriodicalIF":4.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell multi-omics reveals SLC2A1-driven glycolytic reprogramming of pulmonary endothelial cells in sepsis-associated lung injury","authors":"Dingde Long ,&nbsp;Ziyun Lu ,&nbsp;Bei Fang ,&nbsp;Ying Tian ,&nbsp;Huan Fu ,&nbsp;Yang Dong ,&nbsp;Tianyuan Li","doi":"10.1016/j.bbadis.2025.168050","DOIUrl":"10.1016/j.bbadis.2025.168050","url":null,"abstract":"<div><div>Sepsis-induced lung injury is driven by pathological remodeling of pulmonary microvascular endothelial cells (PMVECs), yet the metabolic underpinnings of endothelial dysfunction remain poorly understood. Using single-cell multi-omics analysis of PMVECs from septic patients, we identified profound metabolic reprogramming dominated by glycolysis upregulation, orchestrated through the HIF-1/PI3K-Akt signaling axis. Integrated bioinformatics (Seurat/WGCNA) and experimental validation in a murine sepsis model revealed that SLC2A1-mediated glycolytic flux sustains PMVEC dysfunction, exacerbating tissue inflammation, apoptosis, and fibrosis. Targeted inhibition of glycolysis via SLC2A1 siRNA attenuated metabolic stress, evidenced by reduced extracellular acidification rate (Seahorse) and tricarboxylic acid cycle suppression (metabolomics), while restoring endothelial proliferation, migration, and VEGF/HIF1A homeostasis. Mechanistically, glycolytic inhibition decreased leukocyte infiltration (IHC) and alveolar damage, correlating with improved lung repair metrics. This study establishes PMVEC glycolysis as a keystone of sepsis-associated acute lung injury (ALI), where metabolic reprogramming transitions from adaptive survival signaling to maladaptive tissue injury. Our findings highlight SLC2A1-driven glycolytic pathways as actionable targets for mitigating endothelial dysfunction and advancing metabolic intervention strategies in septic ALI.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 1","pages":"Article 168050"},"PeriodicalIF":4.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145066736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}