Non-alcoholic steatohepatitis (NASH) is a primary cause of cirrhosis and hepatocellular carcinoma. Unfortunately, there is no approved drug treatment for NASH. AMP-activated kinase (AMPK) is an important metabolic sensor and whole-body regulator. It has been proposed that AMPK activators could be used for treating metabolic diseases such as obesity, type 2 diabetes and NASH. In this study, we screened a marine natural compound library by monitoring AMPK activity and found a potent AMPK activator, candidusin A (CHNQD-0803). Further studies showed thatCHNQD-0803directly binds recombinant AMPK with aKDvalue of 4.728 × 10–8M and activates AMPK at both molecular and intracellular levels. We then investigated the roles and mechanisms ofCHNQD-0803in PA-induced fat deposition, LPS-stimulated inflammation, TGF-β-induced fibrosis cell models and the MCD-induced mouse model of NASH. The results showed thatCHNQD-0803inhibited the expression of adipogenesis genes and reduced fat deposition, negatively regulated the NF-κB-TNFα inflammatory axis to suppress inflammation, and ameliorated liver injury and fibrosis. These data indicate thatCHNQD-0803as an AMPK activator is a novel potential therapeutic candidate for NASH treatment.Supplementary InformationThe online version contains supplementary material available at 10.1007/s42995-023-00168-z.