Simvastatin Targets <scp>PKM2</scp> to Alter Metabolic Reprogramming in Hepatic Stellate Cells and Mitigate Liver Fibrosis

ABSTRACT Hepatic stellate cell (HSC) activation plays a crucial role in liver fibrosis progression, with glycolysis and glutaminolysis serving as key components of metabolic reprogramming to sustain HSC activation. Simvastatin (SV) has been shown to ameliorate liver fibrosis; however, its underlying mechanisms remain unclear. This study aimed to explore the protective effects of SV on liver fibrosis with a focus on metabolic regulation. A carbon tetrachloride (CCl 4 )‐induced liver fibrosis model was established in mice, and SV was administered via gavage. LX‐2 cells were used for in vitro mechanistic studies. Our findings demonstrated that SV effectively suppressed aerobic glycolysis and glutaminolysis in activated HSCs. Mechanistically, SV inhibited the PKM2/STAT3/c‐MYC pathway by targeting PKM2, leading to reduced c‐MYC expression. This downregulation of c‐MYC decreased ASCT2 expression, a key transporter in glutamine metabolism, thereby impairing glutamine utilization. These results provide new insights into the metabolic regulatory mechanisms of SV in liver fibrosis and lay the foundation for further exploration of its therapeutic potential in liver disease.