Mevalonate pathway promotes liver cancer by suppressing ferroptosis through CoQ10 production and selenocysteine-tRNA modification

Current therapies show limited efficacy for advanced hepatocellular carcinoma (HCC). This study demonstrates that targeting the mevalonate pathway induces ferroptosis in HCC by disrupting CoQ10 biosynthesis and selenoprotein translation. Clinically relevant inhibitors, such as atorvastatin and the MVD inhibitor 6-FMEV, effectively suppressed tumor growth across multiple HCC subtypes in preclinical models. Furthermore, combining mevalonate pathway inhibitors with tyrosine kinase inhibitors or immune checkpoint inhibitors enhanced anti-tumor efficacy. These findings underscore the translational potential of mevalonate pathway inhibition as a novel therapeutic strategy for HCC.