Abstract

Liver fibrosis is marked by hepatic stellate cell (HSC) activation and increased glucose consumption. Focal adhesion kinase (FAK) upregulates c-Myc expression in HSCs, promoting aerobic glycolysis. This study explores how FAK promotes HSC activation and glycolysis via TRIM25. Immunohistochemistry (IHC) and Western blotting assessed the expression of FAK, TRIM25, FBXW7, c-Myc, and glycolysis-related proteins in human liver tissues and mouse models. Protein interactions were identified by co-immunoprecipitation (Co-IP) and LC-MS, and FAK and TRIM25 localization was observed by immunofluorescence. FAK inhibition reduced LX-2 cell activation, migration, and glycolysis. Co-IP and immunofluorescence confirmed FAK-TRIM25 interaction. FAK inhibits FBXW7-mediated c-Myc ubiquitination and enhances glycolysis by binding TRIM25’s RING, B-BOX, and SPRY regions. Inhibition of FAK improved liver fibrosis and glycolysis. FAK promotes HSC glycolysis through TRIM25 interaction, and its inhibition mitigates liver fibrosis, suggesting a potential therapeutic target.