Hepatoprotection by Ginsenoside Rg1 in alcoholic liver disease

•Treatment with G-Rg1 can ameliorate liver injury in a mouse model of alcoholic hepatitis (AH).•G-Rg1 blocks the up-regulation of CYP2E1 and generation of ROS following alcohol consumption.•G-Rg1 inhibits NLRP3 inflammasome activation and inflammatory cytokine production in AH.•Identified drugable pathways for the development of novel therapies for AH. Alcoholic hepatitis (AH) has caused serious mortality to the world’s population. Despite tremendous efforts to reduce disease burden, effective treatments for this disease are still lacking. Ginsenoside Rg1 (G-Rg1) has been reported to be hepatoprotective in several liver injury models. However, therapeutic potential of this drug in AH has not been tested. In this study, using a chronic ethanol-feeding model, we found that ethanol-fed mice presented clinical indicators of liver injury, such as elevated serum levels of alanine transaminase (ALT), aspartate aminotransferase (AST) and total bilirubin (Tbil), as well as development of hepatic steatosis. Upon treatment with G-Rg1, animals showed marked decreases in serum biochemical parameters, as well as improvement in liver histology. Mechanistically, G-Rg1 blocked the induction of cytochrome P4502E1 (CYP2E1), and prevented the generation of reactive oxygen species (ROS), mitochondria damage, as well as hepatocellular apoptosis. As a result, NLRP3 inflammasome activation was inhibited, which subsequently suppressed the production of active caspase-1 and inflammatory cytokines. Our data has demonstrated a hepatoprotective role for G-Rg1 in AH, and identified potential drugable pathways to improve disease outcomes. These findings may have significant implications for developing novel therapies for inflammatory liver diseases.