Dehydroeburicoic Acid, a Dual Inhibitor against Oxidative Stress in Alcoholic Liver Disease.

Alcoholic liver disease (ALD) is a complicated disease which can lead to hepatocellular carcinoma; however, there is a lack of satisfactory therapeutics. Dehydroeburicoic acid (DEA) ( 1 ), a triterpenoid isolated from Antrodia cinnamomea , has been reported to act against ALD, but its mechanisms of action are still not clear. In this study, we report for the first time the use of DEA ( 1 ) as a dual inhibitor of the Keap1-Nrf2 protein-protein interaction (PPI) and GSK3β in an in vitro ALD cell model. DEA ( 1 ) engages Keap1 to disrupt the Keap1-Nrf2 PPI and inhibits GSK3β to restore Nrf2 activity in a Keap1-independent fashion. DEA ( 1 ) promotes Nrf2 nuclear translocation to activate downstream antioxidant genes. Importantly, DEA ( 1 ) restores the mitochondrial dysfunction induced by ethanol and generates antioxidant activity in the ALD cell model with minimal toxicity. We anticipate that DEA ( 1 ) could be a potential scaffold for the further development of clinical agents for treating ALD.