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This study focused on the mechanistic aspects of salsalate activity against non\u2010alcoholic fatty liver disease (NAFLD). Using high\u2010fat diet (HFD) fed mice, we showed that salsalate treatment decreased body\u2010weight gains, reduced white adipose tissue mass and improved glycaemic control. Mice in salsalate\u2010treated group also had reduced obese adipose tissue and hepatic macrophage infiltration and inflammation and adipogenesis gene expression. Histology analysis revealed predominant decreases in hepatosteatosis, including both macrovesicular and microvesicular steatoses. The treatment reversed AMPK activity repression that was accompanied by reduced caspase\u20106 activity and cleavage. Enzymatic assay and cell culture studies showed that salsalate promoted AMPK activation by directly activating AMPK. 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