AMPK activation prevents hepatocellular carcinoma development through inhibition of HNF4α activity

Abstract Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality and is largely driven by metabolic disorders such as obesity and Type 2 Diabetes. The AMP-activated protein kinase (AMPK) is a master regulator of metabolism, coordinating glucose and lipid metabolism, and its activation has been proposed as a therapeutic strategy for treating metabolic disorders. However, while AMPK activity has been reported to be downregulated in HCC, the precise role of AMPK in HCC development has not been clearly delineated. Here, we investigated the ability of AMPK activation to prevent HCC development using genetic models and specific allosteric AMPK activators. By leveraging a constitutively active AMPK transgenic mouse model and a pharmacological AMPK activator, we were able to elucidate the direct effects of AMPK activation on HCC development and progression. We observed that AMPK activation significantly reduced tumor formation in both diethylnitrosamine (DEN)-induced and streptozocin-induced (STAM) models of HCC. Our findings further implicate bile acid metabolism and hepatic nuclear factor alpha (HNF4α) signaling in the mechanism of AMPK-dependent HCC prevention. These findings provide mechanistic insights into AMPK biology and highlight the potential of AMPK as a therapeutic target, emphasizing the intricate interplay between metabolic dysregulation and cancer development.