Licochalcone A Ameliorates Metabolic-Associated Fatty Liver Disease by AMPK Signaling Pathway Activation through O-GlcNAcylation Regulation and Remodeling of Gut Microbiota and Associated Metabolites

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Metabolic-associated fatty liver disease (MAFLD) is a major global chronic liver disorder with serious health risks. Licorice-derived licochalcone A (LA) exhibits protective activities against multiple chronic conditions. Herein, we investigated the preventive and therapeutic effects of LA on MAFLD. LA alleviated hepatic lipid accumulation, oxidative stress, and inflammation in MAFLD mice, and activated the AMPK pathway via O-GlcNAcylation. Furthermore, LA treatment restored intestinal barrier function and reshaped gut microbiota, elevating the relative abundance of Muribaculaceae and Parasutterella. Gut microbiota depletion and FMT assays demonstrated that gut microbiota are indispensable for LA-mediated MAFLD amelioration and hepatic O-GlcNAcylation regulation. Dodecanedioic acid (DA), a lipid-metabolism-related metabolite, improved MAFLD through AMPK activation. In vitro assays confirmed that LA and DA inhibited AMPK O-GlcNAcylation to boost AMPK phosphorylation and reduce cellular lipid deposition. These results offer new mechanistic perspectives regarding the hepatoprotective properties of LA and confirm its therapeutic potential to treat MAFLD.