Excessive fatty acids in hepatocytes increase the production of lipotoxic species, which then lead to the secretion of reactive oxygen species, damage-associated molecular patterns, and pro-fibrotic mediators. The response activates hepatic HSCs, a major cause of hepatic fibrosis. Activation of HSCs promotes the differentiation of HSCs into myofibroblasts, inducing abnormal accumulation of extracellular matrix proteins.In this study, we tried to validate the potential of AMPK as a therapeutic target for MASH treatment. We discovered that YK activates AMPK by directly binding to the AMP binding site of the AMPK γ-subunit. In choline-deficient high-fat diet mice, we confirmed that YK not only attenuates steatosis but also suppresses the progression of MASH by reducing lipid accumulation, fibrosis. Furthermore, YK reduced lipid accumulation in hepatocytes. In line with these observations in hepatocytes, YK also significantly inhibited the activation of HSCs. Overall, our studies demonstrate that YK, a novel AMPK direct activator, inhibits hepatic fibrosis.