Ginsenoside Rh4 activates AMPK and alleviates NFκB-mediated inflammation in hyperlipidemic hepatopathy

AMP-activated protein kinase (AMPK) regulates lipid metabolism and mitochondrial function in hepatocytes and plays a critical role in liver diseases including hyperlipidemic hepatopathy. Thus, targeting AMPK may represent a potential avenue for treating hyperlipidemic hepatopathy. Herein, we employed molecular docking to screen nine common ginsenosides and identified ginsenoside Rh4 (Rh4) as a potent AMPK activator. While Rh4 is known for its anticancer properties, its effects on hyperlipidemic hepatopathy have not been explored. We subsequently evaluated its efficacy and underlying mechanisms using a poloxamer 407-induced mouse model and a palmitic acid-treated HepG2 cell model. We found that Rh4 significantly improved hyperlipidemic hepatopathy both in vivo and in vitro by upregulating AMPK phosphorylation, preventing mitochondrial dysfunction, reducing lipid accumulation, and attenuating oxidative stress, along with alleviating nuclear factor kappa-B (NFκB)-mediated inflammation. More importantly, Rh4 stabilized the AMPK–NFκB complex in the cytoplasm by binding to AMPK, thereby disrupting NFκB nuclear translocation and suppressing the transcription of pro-inflammatory genes. An AMPK inhibitor markedly diminished the benefits of Rh4 on these pathways. These findings suggest that Rh4 may serve as a promising therapeutic agent for hyperlipidemic hepatopathy by activating AMPK.