Hepatoprotective effect of esculetin on ethanol-induced liver injury in human HepG2 cells and C57BL/6J mice

•Protective effect of esculetin against ethanol-induced liver injury was investigated.•Esculetin significantly prevented ethanol-induced cytotoxicity in HepG2 cells.•Esculetin markedly prevented ethanol-induced liver injury in mice.•Esculetin could be used as a dietary therapy for the prevention of alcoholic liver disease. The objective of this study was to investigate the protective effect of esculetin against ethanol-induced liver injury in both HepG2 cells and mice. Treatment with esculetin significantly prevented ethanol-induced cytotoxicity in HepG2 cells by reducing the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). This protective effect was likely associated with antioxidant potential of esculetin, as evidenced by the attenuation of reactive oxygen species (ROS) and malondialdehyde (MDA) production and restoration of the depleted glutathione (GSH) levels in ethanol-induced HepG2 cells. Esculetin also dramatically increased the nuclear translocation of NF-E2-related factor 2 (Nrf2) and antioxidant response element (ARE) reporter gene activity, which led to the upregulation of ARE-responsive enzymes. In animal studies, esculetin markedly prevented ethanol-induced liver injury by reducing GSH depletion, MDA production, and the lipid contents in liver. Moreover, esculetin lowered the levels of serum ALT, serum AST, and the content of serum lipids.