Verbenalin attenuates hepatic damage and mitochondrial dysfunction in alcohol-associated steatohepatitis by regulating MDMX/PPARα-mediated ferroptosis

Alcoholic steatohepatitis (ASH) is one of the predominant causes of liver-related morbidity and mortality worldwide. However, effective therapy for ASH is still lacking. Notably, increasing evidence indicates ferroptosis may counteract the injury of the ASH. We recently identified a novel strategy for attenuating ASH by an effective adjuvant via ferroptosis through targeting MDMX. Verbenalin, which is a major compound in Verbena officials L (Verbenaceae), is generally recognized as a kind of safe food by the U.S. Food and Drug Administration. In this study, we found for the first time that Verbenalin is protective against alcoholic liver injury through transmission electron microscopy, Fe2+ content detection and other research methods. Its effect can not only inhibit oxidative stress such as MDA, SOD, GSH, ROS, 4-HNE and other related indicators, but also inhibit the ferroptosis of hepatocytes caused by alcohol. It was further confirmed by computer docking that verbenalin was targeted to inhibit MDMX activity, promote PPAR-alpha activation, and inhibit alcohol-induced ferroptosis in hepatocytes. Hence, Verbenalin might be employed as a promising natural supplement for alcoholic liver injury drug therapy.