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

Abstract

Background & aims: Ferroptosis represents a novel therapeutic approach for HCC. HCC cells rely on glutathione/GPX4 and CoQ10/FSP1 to counteract ferroptosis. The mevalonate pathway enzyme, MVD, generates metabolite IPP to mediate selenocysteine-tRNA modification and CoQ10 production. Here, we investigate the role of mevalonate pathway and uncover novel therapeutic targets for HCC.

Methods: Clinical relevance was evaluated in human HCC. MVD regulator was investigated by Chromatin-immunoprecipitation. Targeted metabolomics was performed. Selenoprotein translation was determined by ribosome and polysome profilings. Multiple HCC models examined the efficacy of mevalonate pathway inhibitors.

Results: MVD was over-expressed in human HCC. Blocking MVD by inhibitor, 6-FMEV, reduced IPP and CoQ10 levels while suppressing selenoprotein translation, leading to ferroptosis. Genetic ablation of TRSP (encodes selenocysteine-tRNA) or TRIT1 (i⁶A writer) blocked selenoprotein translation and induced ferroptosis in HCC. In vivo, 6-FMEV or atorvastatin, the inhibitor for upstream mevalonate pathway, suppressed HCC growth, even in steatotic HCC. The pathway inhibitors exhibited synergistic effects when combined with tyrosine kinase inhibitors or anti-PD1 treatment.

Conclusions: We unraveled the intriguing relationship between the mevalonate pathway, CoQ10 production, and selenoprotein translation. The anti-tumor roles of 6-FMEV and atorvastatin highlight the potential of targeting the pathway as a promising therapeutic strategy for HCC.

Impact and implications: Current treatments show limited efficacy in advanced HCC. This study provides evidence that targeting the mevalonate pathway promotes ferroptosis in HCC by impairing CoQ10 synthesis and selenoprotein translation. Clinically, repurposing atorvastatin or MVD inhibitor 6-FMEV inhibits tumor growth across various HCC subtypes in animal models. Moreover, combining the mevalonate pathway inhibitors with TKIs or ICIs enhances the anti-tumor role, highlighting the translational potential of our study.

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