The FASEB Journal最新文献

{"title":"Role of Atypical MAPK p38 Signaling in the Progression of Influenza A-Induced Acute Lung Injury","authors":"Jeremy C. Burton,&nbsp;Denise L. Fahey,&nbsp;Fredejah T. Royer,&nbsp;Yin Zhu,&nbsp;Kaori Sakamoto,&nbsp;Duo Zhang,&nbsp;Wendy T. Watford,&nbsp;Neil J. Grimsey","doi":"10.1096/fj.202501156RR","DOIUrl":"10.1096/fj.202501156RR","url":null,"abstract":"<p>Mitogen-activated protein kinase (MAPK) p38 plays a key role in driving the pathology of acute lung injury (ALI), but effective therapeutic targeting remains elusive. Atypical p38 signaling, mediated by interaction with the adaptor protein Tumor Growth Factor β Activated Kinase 1 (TAK1) Binding Protein 1 (TAB1), has so far only been observed during pathological responses, representing a selective and alternative target during pulmonary injury. However, atypical signaling has not been investigated in the context of pulmonary injury and immune responses related to the onset and progression of ALI. Here, we utilized a genetic knock-in mouse to block influenza A-induced lung injury mediated by atypical signaling. We report that the loss of TAB1-p38 interaction reduces weight loss and recovery time, reduces histopathological scores associated with influenza-induced lung injury early during infection, and prompts earlier recruitment of monocytes to the lungs following infection. These results were found to be independent of viral replication and infectivity, representing the first evidence for the roles of atypical signaling as a driver of host-mediated pulmonary injury following influenza infection.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501156RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145132318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myosin Light Chain Kinase–Mediated Endothelial Hyperpermeability Underlies Temsirolimus-Induced Lung Injury","authors":"Xiaolin Chen,&nbsp;Jianhui Chen,&nbsp;Shuihong Liu,&nbsp;Danjing Yu","doi":"10.1096/fj.202501447R","DOIUrl":"10.1096/fj.202501447R","url":null,"abstract":"<div>\u0000 \u0000 <p>Pulmonary toxicity is a common adverse effect of temsirolimus (a first-generation mammalian target of rapamycin (mTOR) inhibitor), but its mechanisms are unclear. Disruption of endothelial-barrier integrity is key in the pathophysiology of lung injury. We investigated the role and mechanisms of endothelial-barrier dysfunction in the pathogenesis of temsirolimus-induced lung injury. We evaluated the impact of temsirolimus on the permeability of human pulmonary microvascular endothelial cells (HPMECs) using transendothelial electrical resistance and albumin leakage while simultaneously investigating its effects on Ca²⁺ release via ryanodine receptors (RyRs) in endothelial cells (ECs). The roles of myosin light chain kinase (MLCK) in endothelial-barrier permeability were studied in MLCK small interfering (si)RNA-transfected HPMECs. In addition, we established a mouse model subjected to intraperitoneal injections of temsirolimus to explore its effects on pulmonary vascular permeability and lung injury. We highlighted the contribution of the MLCK to temsirolimus-induced vascular hyperpermeability and lung injury, supported by studies in two lines of transgenic mice with knocking out MLCK or conditional deletion of MLCK in the endothelium. Temsirolimus increased the permeability of HPMECs, which was correlated with the phosphorylation of myosin light chain (MLC), MLCK activation, and the formation of F-actin stress fibers. Temsirolimus caused a rise in intracellular Ca²⁺ leakage within HPMECs, an effect that was reversed by pretreatment with ryanodine. The latter diminished the phosphorylation of MLCK/MLC induced by temsirolimus, which subsequently led to disruption of the endothelial barrier in HPMECs. Aligning with these in vitro findings, temsirolimus administration resulted in dysfunction of the lung–vascular barrier, characterized by increased protein levels in bronchoalveolar lavage fluid (BALF) and increased permeability of the lung capillary endothelium. Mice with systemic and EC-specific MLCK knockout exhibited reduced temsirolimus-induced pulmonary microvascular hyperpermeability and lung injury. Temsirolimus induced pulmonary endothelial hyperpermeability mediated (at least in part) by the Ca²⁺-dependent MLCK/p-MLC pathway caused EC contraction and contributed to lung injury through mTOR-independent mechanisms.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145132277","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":"Correction to “High Molecular Crowding in Repair Foci Surrounding DNA Breaks, Measured by Fluorescence Lifetime Imaging Microscopy”","authors":"","doi":"10.1096/fj.202503399","DOIUrl":"10.1096/fj.202503399","url":null,"abstract":"<p>\u0000 <span>S. M. Levchenko</span> and <span>J. W. Dobrucki</span>, “ <span>High Molecular Crowding in Repair Foci Surrounding DNA Breaks, Measured by Fluorescence Lifetime Imaging Microscopy</span>,” <i>The FASEB Journal</i> <span>39</span>, no. <span>17</span> (<span>2025</span>): e71010, https://doi.org/10.1096/fj.202501727R.\u0000 </p><p>The original Funding Information was incomplete. The correct text is:</p><p>“This work was supported by the Polish National Science Center, 2017/27/B/NZ3/01065. The open-access publication has been supported by the Faculty of Biochemistry, Biophysics and Biotechnology under the Strategic Programme Excellence Initiative at Jagiellonian University, Kraków, Poland.”</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202503399","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145132339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of the Impact of Tryptophan-Metabolizing Enzymes and Kynurenic Acid on Antibody-Mediated Glomerulonephritis","authors":"Ryosuke Umeda,&nbsp;Yoshimasa Ito,&nbsp;Shun Minatoguchi,&nbsp;Shigehisa Koide,&nbsp;Kazuo Takahashi,&nbsp;Hiroki Hayashi,&nbsp;Midori Hasegawa,&nbsp;Yukio Yuzawa,&nbsp;Yasuko Yamamoto,&nbsp;Kuniaki Saito,&nbsp;Naotake Tsuboi","doi":"10.1096/fj.202501800R","DOIUrl":"10.1096/fj.202501800R","url":null,"abstract":"<p>Tryptophan (TRP) metabolism through the kynurenine pathway generates multiple biologically active metabolites with diverse immunomodulatory effects, but their roles in glomerulonephritis (GN), particularly in innate immunity, remain poorly understood. Using a nephrotoxic serum-induced GN (NTS-GN) model, we first analyzed mice deficient in key TRP-metabolizing enzymes of the kynurenine pathway: Indoleamine 2,3-dioxygenase 1 and 2 (IDO1 and IDO2), and kynurenine 3-monooxygenase (KMO), and found that <i>Ido1</i>-deficient mice exhibited exacerbated kidney injury and glomerular neutrophil infiltration, whereas <i>Ido2</i> deficiency had no significant impact. In contrast, <i>Kmo</i>-deficient mice showed reduced crescent formation. Unexpectedly, the concentration of kynurenic acid (KYNA), a downstream metabolite of IDO1, was elevated in the kidney cortex of <i>Ido1</i>-deficient mice. Exogenous KYNA administration improved survival, ameliorated renal injury, and reduced neutrophil infiltration in <i>Ido1</i>-deficient mice, indicating its protective effect against antibody-mediated injury. Moreover, KYNA suppressed immune complex-mediated neutrophil spreading, attenuated FcγR–dependent Syk phosphorylation, and reduced VEGF secretion in vitro. Our results position KYNA as a key modulator of neutrophil-driven inflammation in antibody-mediated GN. This study uncovers distinct roles for kynurenine pathway enzymes and highlights the TRP–KYNA pathway as a promising immunometabolic target for controlling innate immune responses in GN.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501800R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145126204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms and Pathological Significance of Liquid–Liquid Phase Separation in Bacteria","authors":"Yanxiao Zhao,&nbsp;Enhui Dai,&nbsp;Mentao Zhang,&nbsp;Yifan Wu,&nbsp;Dongjie Sun,&nbsp;Jiabo Ding","doi":"10.1096/fj.202500634RR","DOIUrl":"10.1096/fj.202500634RR","url":null,"abstract":"<p>Liquid–liquid phase separation (LLPS) has emerged as a fundamental regulatory mechanism in bacterial physiology, orchestrating essential cellular processes including gene expression, stress responses, metabolic homeostasis, and biofilm formation. This phenomenon is driven by intrinsically disordered regions (IDRs), multivalent interactions between modular domains, and dynamic protein-nucleic acid associations, with precise modulation by environmental parameters such as temperature, ionic strength, and post-translational modifications (PTMs). The resulting functional condensates confer enhanced environmental adaptability and contribute to antibiotic resistance mechanisms in bacterial populations. These assemblies further impact host-pathogen interactions through modulation of virulence factor expression and immune evasion strategies, thereby complicating infection management. This comprehensive review systematically examines the molecular mechanisms driving LLPS, its dynamic regulatory networks, and physiological functions in bacteria. We evaluate the therapeutic potential of targeting LLPS pathways for antimicrobial development, with particular emphasis on antibiotic resistance regulation and intestinal commensal colonization. Future research should elucidate the mechanistic roles of LLPS-associated biomacromolecules in bacterial physiology, characterize their assembly and disassembly dynamics, and explore their therapeutic applications to establish a theoretical foundation for innovative antimicrobial strategies.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500634RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145126257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Matrix Metalloproteinases as Candidate Antigenic Determinants for Anti-Tumor Autoantibodies in Human Ovarian Cancer: A Post Hoc Analysis","authors":"Christopher Markosian,&nbsp;Alexander M. Ille,&nbsp;Stephen K. Burley,&nbsp;Wadih Arap,&nbsp;Renata Pasqualini","doi":"10.1096/fj.202500739RR","DOIUrl":"10.1096/fj.202500739RR","url":null,"abstract":"<p>Circulating antibodies in patients with cancer can facilitate the identification of accessible epitopes on autoantigens expressed by tumors. To identify previously unrecognized protein targets in ovarian cancer, we computationally assessed a heptapeptide consensus motif (VPELGHE, flanked by two cysteine residues yielding a cyclic nonapeptide under oxidizing conditions) previously discovered via phage display-based epitope mapping of autoantibodies in patients. Eight proteins associated with ovarian cancer encompass amino acid sequences similar to the consensus motif and were, therefore, considered as candidate native autoantigens. Among these candidate targets, however, matrix metalloproteinase 14 (<i>MMP14</i>) demonstrates gene expression that is both high and negatively correlated with survival in ovarian cancer patient cohorts. MMP14 protein levels are also stable in tumor versus non-tumor tissues. Moreover, the corresponding heptapeptide mimic in MMP14 occurs within an α-helical secondary structural element observed in its catalytic domain. These findings demonstrate that a subset of patient-derived autoantibodies may interact with a previously unknown antigenic epitope found in MMP14 and other MMPs, thereby providing opportunities for the development of new targeted agents.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500739RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145126162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apolipoprotein C3 Promotes Angiogenesis in an Inflammatory Mouse Model of Peripheral Artery Disease","authors":"Jordyn M. Thomas,&nbsp;Panashe Bamhare,&nbsp;Jocelyne Mulangala,&nbsp;Christina A. Bursill,&nbsp;Stephen J. Nicholls,&nbsp;Belinda A. Di Bartolo,&nbsp;Kristen J. Bubb","doi":"10.1096/fj.202502155R","DOIUrl":"10.1096/fj.202502155R","url":null,"abstract":"<p>Apolipoprotein C3 (ApoC3) regulates triglyceride metabolism and is associated with accelerated atherogenesis and adverse cardiovascular outcomes. However, its role in peripheral artery disease (PAD) remains unclear. We investigated whether <i>Apoc3</i> deficiency impacts key features of PAD. Vascularization was assessed using an inflammatory periarterial cuff model (21 days) and a hind limb ischemia model (14 days) in male and female <i>Apoc3</i>^+/+ and <i>Apoc3</i>^−/− mice. Neovascularization was also assessed in mice following extracellular matrix (ECM) plug implantation. Isolated human umbilical vein endothelial cells (HUVECs) were co-cultured with ApoC3-stimulated THP-1 monocytes, and tubule formation was assessed. <i>Apoc3</i>-deficient mice demonstrated less neovessel formation around the cuffed femoral artery, with endothelial cell (CD31+) staining reduced by approximately 40% compared to <i>Apoc3</i>^+/+ mice. Twenty-four hours after cuff placement, <i>Apoc3</i>^+/+ vessels exhibited increased expression of angiogenic (<i>Hif1a</i> and <i>Vegf1</i>) and pro-inflammatory (<i>Cd68</i>) markers, while <i>Apoc3</i>-deficient vessels did not. Confirming a role for inflammation in ApoC3-induced angiogenesis, tubulogenesis of HUVECs increased only in the presence of ApoC3 and THP-1 monocytes. <i>Apoc3</i> deficiency, however, did not affect ischemia-driven angiogenesis, as there were no differences in revascularization compared to <i>Apoc3</i>^+/+ mice, as assessed by the perfusion index (laser Doppler), fibrosis (Picrosirius red staining), or the mRNA expression of apoptotic (<i>Bax</i>), angiogenic (<i>Hif1a</i> and <i>Vegf1</i>), and inflammatory (<i>Ccl2</i>, <i>Il6</i>, and <i>Vcam1</i>) markers in the ischemic hind limb. Neovascularization following ECM plug implantation was also unaffected by <i>Apoc3</i> deficiency. In conclusion, ApoC3 contributes to pathological, inflammation-driven angiogenesis, highlighting its potential as a therapeutic target for pathological angiogenesis without inhibiting physiological ischemia-driven angiogenesis.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202502155R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Timosaponin A3 Ameliorates Prostate Cancer Progression via Upregulating STARD4 Mediated Cholesterol Metabolism","authors":"Ye Zhi,&nbsp;Luqi Ge,&nbsp;Shaoru Wang,&nbsp;Wencong Zang,&nbsp;Zhentao Zhang,&nbsp;Tong Xu,&nbsp;Yiwen Zhang,&nbsp;Feifeng Song,&nbsp;Ping Huang","doi":"10.1096/fj.202501885R","DOIUrl":"10.1096/fj.202501885R","url":null,"abstract":"<div>\u0000 \u0000 <p>Prostate cancer (PCa) is a common and aggressive malignancy in men, often diagnosed at advanced stages with a poor five-year survival rate. Despite therapeutic advances, effective treatments for castration-resistant PCa remain lacking. Timosaponin A3 (TA3), a natural steroidal saponin derived from <i>Anemarrhena asphodeloides</i> Bunge, has shown potential anti-tumor properties, but its role in PCa and the underlying mechanisms have not been fully elucidated. In this study, we demonstrate that TA3 significantly inhibits the proliferation, migration, and invasion of PCa cells <i>in vitro</i>, and suppresses tumor growth in xenograft models. Transcriptomic analysis revealed that TA3 exerts its anti-tumor effects by modulating cholesterol metabolism. Elevated cholesterol levels were observed in PCa patients, and exogenous cholesterol administration reduced tumor growth <i>in vivo</i>. Notably, TA3 treatment upregulated the lipid transporter StAR related lipid transfer domain containing 4 (STARD4), a key regulator of cholesterol transport, which was confirmed to mediate the inhibitory effects of TA3 on PCa progression. Overexpression of STARD4 attenuated PCa development both <i>in vitro</i> and <i>in vivo</i>, while STARD4 knockdown abolished these effects. Collectively, our findings suggest that TA3 suppresses PCa progression by enhancing cholesterol metabolism via STARD4 upregulation, supporting its potential as a novel therapeutic agent for prostate cancer.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145110750","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":"Role of Necroptosis and Neuroinflammation in CSVD-Associated Cognitive Decline in db/db Mice","authors":"Dan-Qiong Wang,&nbsp;Lei Wang,&nbsp;Ping Zhao,&nbsp;Yu-Meng Gu,&nbsp;Xiao-Shuang Xia,&nbsp;Tao Li,&nbsp;Na An,&nbsp;Xin Li","doi":"10.1096/fj.202500772R","DOIUrl":"10.1096/fj.202500772R","url":null,"abstract":"<p>Diabetes-related cerebral small-vessel disease (CSVD) is an important causative factor of cognitive impairment, but its molecular mechanisms have not been clarified. The aim of this study was to investigate the role of the necrotic apoptotic pathway (RIP1/RIP3/MLKL) and the inflammatory response in diabetic CSVD. Wild-type C57BL/6 mice and leptin receptor-deficient db/db mice were categorized into six groups according to age (8-, 12-, and 16-week time points) and genotype. Cognitive function was assessed by the water maze experiment (escape latency, percentage of time spent in the target quadrant, and number of times through the table); cerebral atrophy and ventricular dilatation were detected by cranial MRI; cerebral microvascular structure, cortical neuronal damage, and ultrapathological changes in hippocampal mitochondria were observed by HE staining and transmission electron microscopy, respectively; and blood–brain barrier-associated proteins were detected by western blot and RT-qPCR (occludin, ZO-1, VEGFA) and necroptotic apoptotic pathway molecules (RIP1, RIP3, MLKL). Western blot and RT-qPCR were used to detect the protein and mRNA expression of blood–brain barrier-associated proteins (occludin, ZO-1, VEGFA) and necroptotic apoptotic pathway molecules (RIP1, RIP3, MLKL). Immunohistochemistry was used to localize the distribution of RIP1/RIP3/MLKL in the brain tissues; and plasma levels of inflammatory factors (IL-6, IL-10, TNF-α, NF-κB) were quantified by ELISA. In db/db mice: (1) spatial learning and memory abilities were reduced compared to wild-type (WT) mice; (2) at 16 weeks of age, db/db mice showed signs of temporal lobe atrophy and an enlarged fourth cerebral ventricle; (3) capillary proliferation and cortical injury were observed in the frontal cortex, along with mitochondrial swelling, degeneration, and nuclear membrane rupture in hippocampal cells; (4) the occludin and ZO-1 protein expression in the db/db-16W group decreased to 0.48- and 0.68-fold of the WT-8W group, respectively, and the VEGFA was elevated by 2.87-fold; the mRNA expression of RIP1/RIP3/MLKL was up-regulated to 3.02-, 3.12-, and 4.02-fold of the WT group, the relative expression of western blot proteins increased synchronously; the increase in the number of immunohistochemically positive cells increased synchronously, and (5) plasma inflammatory factors were significantly elevated in db/db mice: IL-6 ↑3.81-fold, TNF-α ↑4.23-fold, NF-κB ↑3.56-fold. This study reveals for the first time the molecular mechanism by which diabetes drives cerebral small vessel disease (CSVD) through the spatiotemporal-dependent activation of the necrotic apoptotic pathway (RIP1/RIP3/MLKL), and targeting the necrotic apoptotic pathway may serve as a potential therapeutic strategy for diabetes-associated cognitive deficits by concurrently protecting the blood–brain barrier and suppressing neuroinflammation.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500772R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145110739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Gut–Spleen Axis in Liver Disease: Mechanistic Insights Into Metabolism, Metabolome, and Microbiome Interactions","authors":"Priyankar Dey","doi":"10.1096/fj.202502523RR","DOIUrl":"10.1096/fj.202502523RR","url":null,"abstract":"<div>\u0000 \u0000 <p>This review consolidates existing knowledge on the gut–spleen axis and its pivotal role in the pathophysiology of metabolic liver disease by summarizing the interconnected tripartite network connecting the gut, spleen, and liver through vascular, lymphatic, and neurological pathways, emphasizing the role of the spleen as an active mediator rather than a passive participant. Gut dysbiosis and impaired intestinal barrier function promote the translocation of microbial metabolites (e.g., short-chain fatty acids, bile acids, lipopolysaccharides) to the spleen through the portal vein. Splenic immune cells react by secreting proinflammatory cytokines (e.g., TNF-α, IL-6) and profibrogenic mediators (e.g., TGF-β1), which intensify hepatic inflammation, fibrosis, and hinder regeneration. Splenomegaly and hypersplenism in cirrhosis exacerbate liver damage through feedback loops mediated by portal hypertension. The mesenteric immune system and vagus nerve act as crucial mediators in gut–spleen communication, regulating systemic immunometabolic responses. Significantly, splenic dysfunction exacerbates liver pathology by providing fibrogenic immune cells to the liver and impacting hepatocyte regeneration. Therapeutic approaches aimed at gut microbiota (e.g., probiotics, prebiotics), barrier integrity, or splenic immune function (e.g., splenectomy) may interrupt this pathogenic pathway. Future research needs to elucidate the molecular pathways by which microbial metabolites affect splenic cells and validate translational therapies to alleviate disease progression driven by the gut–spleen–liver axis.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202502523RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}