Protective Effects of Leonurine on Alcoholic Liver Injury Through Modulation of Oxidative Stress and JAK2-STAT3...

Alcoholic liver disease (ALD) is a prevalent and progressive hepatic disorder driven by chronic excessive alcohol consumption. Leonurine (LH), a bioactive alkaloid isolated from Herba Leonuri, possesses well-documented antioxidant and cytoprotective properties. This study comprehensively investigated the hepatoprotective efficacy of LH against ethanol-induced liver injury and mechanistically dissected its molecular underpinnings. Antioxidant capacity and cytoprotective activity were assessed in ethanol-treated hepatocytes. Network pharmacology and gene expression analysis were performed to identify potential therapeutic targets and signaling pathways. UHPLC-MS/MS-based metabolomics was applied to characterize endogenous metabolic alterations induced by LH. LH demonstrated significant antioxidant activity and was predicted to interact with 44 ALD-related targets. Functional enrichment and gene validation analyses revealed that its protective effects were primarily associated with regulation of the JAK2-STAT3 signaling pathway. Metabolomic profiling identified 48 differential metabolites and 25 significantly affected metabolic pathways. Integrated analysis of metabolites and target genes further supported the JAK-STAT signaling pathway as a central regulatory axis, which was confirmed in cellular experiments. Collectively, these results demonstrate that LH confers hepatoprotection in ALD primarily through modulation of the JAK2-STAT3 signaling pathway, underscoring its translational promise as a mechanism-informed therapeutic candidate.