LAUSR

Ferroptosis is a novel immunogenic and regulated cell death caused by iron-dependent lipid peroxidation. Glutathione peroxidase 4(GPX4)/glutathione and ferroptosis suppressor protein 1(FSP1)/Coenzyme Q10(CoQ10) are two major anti-ferroptosis systems that prevent lipid ROS-induced cell death. Our current study unprecedentedly uncovered that the Mevalonate pathway (MVA) protects HCC from ferroptosis by two parallel mechanisms: 1) by providing the lipophilic antioxidant CoQ10 for FSP1; 2) by generating isopentenyl pyrophosphate (IPP), a substrate for Selenocysteine (Sec)-tRNA modification for selenoprotein GPX4 translation. Selenoproteins are a class of proteins composed of selenocysteine, the 21st amino acid not found in the codon table. Selenocysteine is recoded by the stop codon UGA and synthesized on its tRNA. The Sec-tRNA incorporates Sec into selenoproteins such as GPX4. We showed that perturbation of the MVA pathway by genetic knockdown or pharmacologic inhibition repressed CoQ10 synthesis and the translation of selenoproteins, thereby leading to lipid-derived ROS and ferroptotic cell death. Furthermore, we showed that Mevalonate diphosphate decarboxylase (MVD), a MVA enzyme, was a transcriptional target of Nuclear Factor Erythroid 2- related factor 2 (NRF2), a master regulator of oxidative stress response. High expression of MVD was associated with poor prognosis in HCC. Strikingly, MVD inhibitor treatment profoundly suppressed HCC. Reduced tumor size and increased tumor-infiltrated effector T cells and macrophages were found in vivo. To conclude, our study has provided novel mechanistic insight about how NRF2/MVA pathway promotes HCC and suggested that MVD might be a good prognostic indicator and therapeutic target in human HCC. Funding Support: RGC Postdoctoral Fellowship Scheme 2021/22 (Project #102010048) Citation Format: Yiling Chen, Derek Lee, Misty Shuo Zhang, Jacinth Wing-Sum Cheu, Carmen Chak-Lui Wong. Targeting the mevalonate pathway, a novel anti-ferroptosis pathway, in hepatocellular carcinoma (HCC) treatment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3675.