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Transcriptomic analyses of human and murine models of MASH revealed consistent upregulation of ITGB3 in hepatocytes. In mice, the hepatocyte\u2010specific overexpression of ITGB3 exacerbates diet\u2010induced obesity, insulin resistance, steatosis, and fibrosis, the deletion of ITGB3 alleviates these phenotypes. Additionally, the overexpression of DHHC5 reversed the hallmarks of MASH in ITGB3\u2010deficient mice, confirming the central role of DHHC5 in this process. Mechanistically, ITGB3 is a novel \u201caccelerator\u201d that directly increases CD36\u2010mediated fatty acid uptake by recruiting LYN, then modulating LYN protein stability, and triggering LYN proteasomal degradation. This degradation relieves LYN\u2013mediated inhibition of DHHC5 and promotes ITGB3\/DHHC5\/CD36 complex formation, thereby enhancing DHHC5\u2010dependent CD36 palmitoylation and subsequent CD36\u2010mediated fatty acid uptake. Pharmacologic inhibition of ITGB3 using cyclic\u2010RGDfk peptide improved serum lipid profiles and hepatic steatosis. This study uncovers a previously unrecognized mechanism by which ITGB3 acts as a driver of hepatic steatosis of hepatic steatosis. Targeted intervention against ITGB3 to modulate CD36\u2010mediated lipid uptake may represent a novel therapeutic strategy for the treatment of MASH.<\/jats:p>","DOI":"10.1002\/advs.202517455","type":"journal-article","created":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T03:49:57Z","timestamp":1765252197000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrin \u03b23 Orchestrates Hepatic Steatosis via a Novel CD36\u2010Dependent Lipid Uptake Complex"],"prefix":"10.1002","volume":"13","author":[{"given":"Ying","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Cardiology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan Hubei 430030 China"},{"name":"Hubei Provincial Engineering Research Center of Vascular Interventional Therapy  Wuhan Hubei 430030 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