Pharmacological Activation of AMP-activated Protein Kinase Ameliorates Liver Fibrosis in a Metabolic...

Metabolic dysfunction-associated steatohepatitis (MASH) is a significant contributor to hepatocellular carcinoma (HCC). To validate AMPK activation as a therapeutic strategy for MASH-associated liver fibrosis, we investigated the effects of a 4-chloro-benzenesulfonamide derivative named KN21, a novel AMPK activator, on the liver fibrogenic process in a MASH model. In mice fed a choline-deficient, L-amino acid-defined, high fat diet (CDAHFD), KN21 reduced hepatic steatosis, lipid accumulation, and liver fibrosis. In hepatocyte cells treated with palmitic acid and oleic acid (PO), KN21 attenuated lipid accumulation and the release of reactive oxygen species (ROS) and fibrotic mediators. Hepatic stellate cells stimulated with hepatocyte-derived conditioned medium (CM) exhibited increased expression of fibrosis markers, whereas hepatic stellate cells exposed to CM from KN21-treated hepatocytes showed a decrease of fibrosis marker expression. Additionally, KN21 inhibited the activation of human hepatic stellate cells and demonstrated potent antifibrotic activity. These findings underscore the therapeutic potential of pharmacological AMPK activation for the treatment of MASH-associated liver fibrosis.