This study looks at a protein called integrin beta‑3 (ITGB3) and shows it makes the liver take up more fat, leading to fatty liver disease. Blocking ITGB3 with a small peptide improved liver health in mice, but the peptide studied is not palmitoyl‑dipeptide‑6 and the work is basic science, not a ready‑to‑use protocol.

In metabolic dysfunction-related steatohepatitis (MASH), ITGB3 promotes hepatic fibrosis via activating hepatic stellate cells, but whether it directly regulates hepatic lipid metabolism through membrane-scaffolding function and the underlying mechanisms remain unclear. Transcriptomic analyses of human and murine models of MASH revealed consistent upregulation of ITGB3 in hepatocytes. In mice, the hepatocyte-specific overexpression of ITGB3 exacerbates diet-induced 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-deficient mice, confirming the central role of DHHC5 in this process. Mechanistically, ITGB3 is a novel "accelerator" that directly increases CD36-mediated fatty acid uptake by recruiting LYN, then modulating LYN protein stability, and triggering LYN proteasomal degradation. This degradation relieves LYN-mediated inhibition of DHHC5 and promotes ITGB3/DHHC5/CD36 complex formation, thereby enhancing DHHC5-dependent CD36 palmitoylation and subsequent CD36-mediated fatty acid uptake. Pharmacologic inhibition of ITGB3 using cyclic-RGDfk 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-mediated lipid uptake may represent a novel therapeutic strategy for the treatment of MASH.