Liver‐specific <scp>BAG3</scp> knockout delays chemically induced hepatocellular carcinoma development

Bcl-2-associated athanogene 3 (BAG3) is a multifunctional protein involved in several cellular processes, including protein folding, degradation, apoptosis regulation, and cytoskeleton dynamics. Its dysregulation has been associated with several pathological conditions, including cancer. Hepatocellular carcinoma (HCC), a leading cause of cancer-related deaths worldwide, represents a complex molecular landscape involving multiple pathways. Pro- and antitumorigenic roles have been suggested for BAG3 in HCC. To elucidate the function of BAG3 in HCC, we established a hepatocyte-specific BAG3 knockout mouse model (BAG3albKO). Histological analysis revealed delayed hepatocarcinogenesis in BAG3albKO mice induced by diethylnitrosamine (DEN) treatment, suggesting a potential role for BAG3 deficiency in modulating liver lesion development. Moreover, BAG3 deletion attenuated cell migration and epithelial-to-mesenchymal transition in HCC-derived murine cell lines, indicating an impact on tumor aggressiveness. Proteomic analysis of DEN-induced acute liver injury revealed alterations in key pathways in BAG3albKO mice livers, including inhibition of autophagy and increased liver necrosis. Collectively, these findings emphasize the complex role of BAG3 in HCC pathogenesis and indicate its participation in tumor onset and progression.