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

Abstract

Background & aims: Ferroptosis has emerged as a promising therapeutic approach for hepatocellular carcinoma (HCC). To evade ferroptosis, HCC cells depend on the glutathione/GPX4 and CoQ10/FSP1 antioxidant systems. The mevalonate pathway enzyme mevalonate diphosphate decarboxylase (MVD) generates isopentenyl pyrophosphate (IPP), which supports both selenocysteine-tRNA modification and CoQ10 biosynthesis. Here, we investigated the role of the mevalonate pathway in HCC and explored novel vulnerabilities for therapeutic targeting.

Methods: The clinical relevance of MVD expression was assessed in human HCC samples. Regulation of MVD was examined using chromatin immunoprecipitation. Targeted metabolomics was performed to measure IPP and CoQ10 levels. Selenoprotein translation was evaluated via ribosome and polysome profiling. Multiple in vitro and in vivo HCC models were used to assess the efficacy of mevalonate pathway inhibitors.

Results: MVD was significantly overexpressed in human HCC tissues. Pharmacological inhibition of MVD using 6-FMEV reduced levels of IPP and CoQ10, suppressed selenoprotein translation, and triggered ferroptosis in HCC cells. Genetic ablation of TRSP (which encodes selenocysteine-tRNA) or TRIT1 (responsible for i⁶A tRNA modification) similarly blocked selenoprotein synthesis and induced ferroptosis. In mouse models, both 6-FMEV and atorvastatin (a clinically approved upstream mevalonate pathway inhibitor) effectively suppressed HCC tumor growth, including steatotic HCC. Moreover, mevalonate pathway inhibition showed synergistic anti-tumor effects when combined with either tyrosine kinase inhibitors or anti-PD-1 immunotherapy.

Conclusions: Our findings reveal a critical link between the mevalonate pathway, CoQ10 production, and selenoprotein translation in protecting HCC cells from ferroptosis. The demonstrated anti-tumor role of 6-FMEV and atorvastatin supports the therapeutic potential of targeting the mevalonate pathway in HCC, either alone or in combination with existing treatments.

Impact and implications: 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.

Keywords: CoQ10; Ferroptosis; GPX4; Mevalonate pathway; Selenoprotein translation; atorvastatin.