Mitochondrial ribosomal protein S30 inhibits ferroptosis and promotes tumor progression in hepatocellular carcinoma via suppressing GPX4 ubiquitination.

Abstract

Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related deaths, with limited therapeutic options. Ferroptosis, an iron-dependent form of cell death characterized by lipid peroxidation, has emerged as a promising approach for HCC intervention due to its close association with multiple aspects of liver cancer, such as proliferation, metastasis, and drug resistance. In this study, we identified the oncogene mitochondrial ribosomal protein S30 (MRPS30) associated with HCC prognosis through multi-omics analysis. Using HCC cell lines with MRPS30 knockdown/overexpression and xenograft tumor models, we confirmed that MRPS30 inhibits ferroptosis by upregulating Glutathione Peroxidase 4(GPX4), thereby promoting the malignant progression of HCC and resistance to lenvatinib. Mechanistically, MRPS30 specifically interacts with GPX4 and inhibits the lysine 48 (K48)-linked ubiquitination of GPX4 to maintain its protein stability. By stabilizing GPX4, MRPS30 reduces malondialdehyde (MDA) accumulation and maintains glutathione (GSH) homeostasis, thereby inhibiting ferroptosis and ultimately enhancing the malignant behaviors and drug resistance of HCC. In conclusion, we identified MRPS30 as a prognosis-related gene in HCC and revealed its role in regulating HCC proliferation, metastasis, and drug resistance through ferroptosis. Our findings uncover a key driver of ferroptosis resistance mediated by the MRPS30/GPX4 axis and further confirm that ferroptosis is a promising therapeutic strategy for HCC treatment.