METTL5 promotes tumor progression and ferroptosis resistance via MGST1 in HCC

Hepatocellular carcinoma (HCC) ranks among the most prevalent cancers globally. Ferroptosis plays a vital role in the resistance of HCC to various cancer treatments. However, the specific molecular mechanisms that inhibit ferroptosis in HCC remain unknown. Therefore, this study aims to elucidate the role of 5, N6-adenosine (METTL5) in regulating HCC development and ferroptosis.

Quantitative real-time polymerase chain reaction, western blotting, and immunohistochemical staining were employed to detect the expression of METTL5 and Microsomal glutathione S-transferase 1 (MGST1) in HCC cell lines and clinical samples. Xenotransplantation experiments were conducted to investigate the effects of METTL5 knockdown on HCC cells in vivo. Tandem mass tagging proteomic quantification was utilized to analyze the downstream targets of METTL5. In vitro functional rescue assays were used to explore the influence of METTL5 and MGST1 on cell functions, including proliferation, migration, invasion, and ferroptosis in HCC cell lines.

METTL5 and MGST1 were aberrantly and highly expressed in HCC tissues than in adjacent normal liver tissues. High expression levels of METTL5 or MGST1 were a prognostic risk factor for patients with HCC. METTL5 regulated the protein expression of MGST1 through its N6-methyladenosine catalytic function. The METTL5-MGST1 axis regulated proliferation, migration, invasion, and suppression of ferroptosis in HCC cells.

Our study explored and confirmed the oncogenic roles of METTL5 and MGST1 in HCC, uncovering a novel mechanism by which the METTL5-MGST1 axis suppresses ferroptosis in HCC. Our findings establish a molecular foundation for developing therapeutic strategies for HCC.