Total glucosides of Picrorhizae Rhizome alleviate non-alcoholic steatohepatitis (NASH) by specifically targeting acyl-CoA oxidase 1

Nonalcoholic steatohepatitis (NASH), a chronic liver disease characterized by the accumulation of fat in the liver, is highly prevalent on a global scale. In this study, we investigated the effects of total glucosides of Picrorhizae Rhizome (TGPR), the primary active ingredients in traditional Chinese herbal medicine derived from <i>Picrorhiza scrophulariiflora</i> Pennell. TGPR is known for its efficiency in attenuating NASH, in mouse models induced by methionine-choline deficient (MCD) diet or high-fat diet (HFD). Our findings indicated that TGPR exhibited efficacy in reducing hepatic steatosis and lowering serum lipid levels, specifically triglyceride and total cholesterol in the NASH model. Meanwhile, TGPR exhibited a suppressive effect on the production of pro-inflammatory cytokines. Mechanistically, we identified acyl-CoA oxidase 1 (Acox1) as a crucial cellular target of TGPR, influencing lipid metabolism and ATP production to treat NASH. Additionally, we found that the major components of TGPR, including Picroside I, Picroside II, and Picroside IV, exhibit significant binding abilities to the target Acox1 at its catalytic C-terminal α-domain, stabilizing its protein expression. TGPR binding to Acox1 facilitated the degradation of fatty acids via the Acox1-mediated MAPK signaling pathways, and consequently plays a role in regulating energy metabolism and reducing liver inflammation. In summary, our study demonstrates that TGPR effectively counteracts NASH by specifically targeting Acox1, thereby providing a significant clinical solution for the treatment of NASH.