{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:04:14Z","timestamp":1790701454981,"version":"4.1.0"},"reference-count":30,"publisher":"IMR Press","issue":"9","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Henan Provincial Natural Science Foundation General Program","award":["262300421625"],"award-info":[{"award-number":["262300421625"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading global health burden, yet the regulatory nodes linking hepatic immune dysregulation to metabolic perturbations remain incompletely understood. Methods: We integrated bulk and single-cell RNA sequencing (scRNA-seq) to identify core regulatory genes dysregulated by a high-fat diet (HFD). The functional role of the candidate gene Arhgap25, was validated using an adeno-associated virus (AAV)-mediated overexpression mouse model and an in vitro Kupffer cell (KC)-hepatocyte co-culture system. Results: Integrated transcriptomic analysis identified Arhgap25 as a key differentially expressed gene consistently upregulated in HFD-fed livers, with specific enrichment in KCs. In vivo, Arhgap25 overexpression significantly promoted macrovesicular steatosis, increased intrahepatic triglycerides and cholesterol levels, and exacerbated liver injury. Mechanistically, Arhgap25 triggered a pro-inflammatory microenvironment by promoting KC polarization toward the M1 phenotype, characterized by increased TNF-\u03b1, IL-6, and IL-1\u03b2 expression and suppression of the M2 marker ARG1. In vitro co-culture assays demonstrated that Arhgap25 exacerbated hepatocellular lipid accumulation and inflammatory responses by promoting the phosphorylation of the AKT\/mTOR signaling axis. AKT inhibition further confirmed this signaling dependency. Conclusion: Our findings establish Arhgap25 as a critical mediator in the hepatic immune-metabolic network. By positively regulating AKT\/mTOR signaling in KCs, Arhgap25 promotes M1 polarization and subsequent metabolic dysfunction, highlighting it as a potential therapeutic target for MASLD.<\/jats:p>","DOI":"10.31083\/fbl53591","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:21:51Z","timestamp":1790698911000},"source":"Crossref","is-referenced-by-count":0,"title":["Arhgap25 Promotes Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) by Driving Kupffer Cell Polarization via Activation of the AKT\/mTOR Signaling Pathway"],"prefix":"10.31083","volume":"31","author":[{"given":"Yan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, 450052 Zhengzhou, Henan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8144-1830","authenticated-orcid":true,"given":"Shuangshuang","family":"Lu","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Zhengzhou University, 450052 Zhengzhou, Henan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Kendall TJ, Jimenez-Ramos M, Turner F, Ramachandran P, Minnier J, McColgan MD, et al. An integrated gene-to-outcome multimodal database for metabolic dysfunction-associated steatotic liver disease. Nature Medicine. 2023; 29: 2939\u20132953.","DOI":"10.1038\/s41591-023-02602-2"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Yu X, Huang C, Evers M, Liu J, Ting HJ, Zhang S, et al. Targeted inhibition of hepatic de novo ceramide synthesis ameliorates MASH. Science Advances. 2025; 11: eadx2681.","DOI":"10.1126\/sciadv.adx2681"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Meng L, Lu F, Zhang B, Ma Y, Gao J. Taming fatty liver: can taurine combat metabolic dysfunction in MASLD? Cell Communication and Signaling : CCS. 2025; 23: 439.","DOI":"10.1186\/s12964-025-02439-x"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Martin-Grau M, Monle\u00f3n D. The Role of Microbiota-Related Co-Metabolites in MASLD Progression: A Narrative Review. 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International Journal of Molecular Sciences. 2022; 23: 12746.","DOI":"10.3390\/ijms232112746"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Tan J, Zhang J, Wang M, Wang Y, Dong M, Ma X, et al. DRAM1 increases the secretion of PKM2-enriched EVs from hepatocytes to promote macrophage activation and disease progression in ALD. Molecular Therapy. Nucleic Acids. 2021; 27: 375\u2013389.","DOI":"10.1016\/j.omtn.2021.12.017"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Dong T, Hu G, Fan Z, Wang H, Gao Y, Wang S, et al. Activation of GPR3-\u03b2-arrestin2-PKM2 pathway in Kupffer cells stimulates glycolysis and inhibits obesity and liver pathogenesis. Nature Communications. 2024; 15: 807.","DOI":"10.1038\/s41467-024-45167-5"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Chan MM, Daemen S, Beatty W, Byrnes K, Cho K, Ferguson D, et al. Induction of TFEB promotes Kupffer cell survival and reduces lipid accumulation in MASLD. Hepatology Communications. 2025; 9: e0853.","DOI":"10.1097\/hc9.0000000000000853"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Elnagdy M, Barve S, McClain C, Gobejishvili L. cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease. Biomolecules. 2020; 10: 1433.","DOI":"10.3390\/biom10101433"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Duan Y, Pan X, Luo J, Xiao X, Li J, Bestman PL, et al. Association of Inflammatory Cytokines With Non-Alcoholic Fatty Liver Disease. Frontiers in Immunology. 2022; 13: 880298.","DOI":"10.3389\/fimmu.2022.880298"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Braunersreuther V, Viviani GL, Mach F, Montecucco F. Role of cytokines and chemokines in non-alcoholic fatty liver disease. 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ARHGAP25, a novel Rac GTPase-activating protein, regulates phagocytosis in human neutrophilic granulocytes. Blood. 2012; 119: 573\u2013582.","DOI":"10.1182\/blood-2010-12-324053"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Huang WK, Chen Y, Su H, Chen TY, Gao J, Liu Y, et al. ARHGAP25 Inhibits Pancreatic Adenocarcinoma Growth by Suppressing Glycolysis via AKT\/mTOR Pathway. International Journal of Biological Sciences. 2021; 17: 1808\u20131820.","DOI":"10.7150\/ijbs.55919"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Cs\u00e9p\u00e1nyi-K\u00f6mi R, Wisniewski \u00c9, Bartos B, L\u00e9vai P, N\u00e9meth T, Bal\u00e1zs B, et al. Rac GTPase Activating Protein ARHGAP25 Regulates Leukocyte Transendothelial Migration in Mice. Journal of Immunology (Baltimore, Md. : 1950). 2016; 197: 2807\u20132815.","DOI":"10.4049\/jimmunol.1502342"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Ribas V, Mor\u00f3n-Ros S, Mar\u00ed H, Gracia-Batllori A, Brugnara L, Herrero-G\u00f3mez A, et al. Diet-induced obesity disrupts sexually dimorphic gene expression in mice. American Journal of Physiology. Cell Physiology. 2025; 329: C987\u2013C1003.","DOI":"10.1152\/ajpcell.00098.2025"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Wu Z, Wang Z, Chang X, Chen X, Ding Q, Fu R, et al. Prioritizing pathway signature using deep learning approach: a novel strategy for traditional Chinese medicine formula generation and optimization. Briefings in Bioinformatics. 2025; 26: bbaf403.","DOI":"10.1093\/bib\/bbaf403"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"Iwata A, Maruyama J, Natsuki S, Nishiyama A, Tamura T, Tanaka M, et al. Egr2 drives the differentiation of Ly6Chi monocytes into fibrosis-promoting macrophages in metabolic dysfunction-associated steatohepatitis in mice. Communications Biology. 2024; 7: 681.","DOI":"10.1038\/s42003-024-06357-5"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Steinberg GR, Valvano CM, De Nardo W, Watt MJ. Integrative metabolism in MASLD and MASH: Pathophysiology and emerging mechanisms. Journal of Hepatology. 2025; 83: 584\u2013595.","DOI":"10.1016\/j.jhep.2025.02.033"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Syed-Abdul MM. Lipid Metabolism in Metabolic-Associated Steatotic Liver Disease (MASLD). Metabolites. 2023; 14: 12.","DOI":"10.3390\/metabo14010012"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Jin J, Cheng K, Chen M, Liang H, Zhang W. Immunotherapy resistance in MASLD-related hepatocellular carcinoma: special immune microenvironment and gut microbiota. International Journal of Biological Sciences. 2025; 21: 5666\u20135690.","DOI":"10.7150\/ijbs.117394"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Zhao H, Wang W, Zhu P, Shi Z. Macrophage-tregs crosstalk: the \"hub\" of the immune network in MASLD. Frontiers in Immunology. 2025; 16: 1680878.","DOI":"10.3389\/fimmu.2025.1680878"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Reue K, Wang H. Mammalian lipin phosphatidic acid phosphatases in lipid synthesis and beyond: metabolic and inflammatory disorders. Journal of Lipid Research. 2019; 60: 728\u2013733.","DOI":"10.1194\/jlr.S091769"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Saadati S, Godini R, Reddy A, Teede H, Mousa A. Metabolic crossroads in insulin resistance: exploring lipid dysregulation and inflammation. Frontiers in Immunology. 2025; 16: 1692742.","DOI":"10.3389\/fimmu.2025.1692742"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Xu S, Lu F, Gao J, Yuan Y. Inflammation-mediated metabolic regulation in adipose tissue. Obesity Reviews : an Official Journal of the International Association for the Study of Obesity. 2024; 25: e13724.","DOI":"10.1111\/obr.13724"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"Saci A, Cantley LC, Carpenter CL. Rac1 regulates the activity of mTORC1 and mTORC2 and controls cellular size. Molecular Cell. 2011; 42: 50\u201361.","DOI":"10.1016\/j.molcel.2011.03.017"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"M\u00e4kitie RE, Henning P, Jiu Y, K\u00e4mpe A, Kogan K, Costantini A, et al. An ARHGAP25 variant links aberrant Rac1 function to early-onset skeletal fragility. 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