PRMT5 inhibits the ferroptosis of hepatocellular carcinoma via regulating RBM15/FTH1 signaling.

Hepatocellular carcinoma (HCC) is one of the most malignant tumors worldwide. This study aimed to investigate the role of protein arginine methyltransferase 5 (PRMT5) in HCC. Gene expression was determined using reverse transcription-quantitative polymerase chain reaction, Western blot, and immunohistochemistry. The interaction between genes were determined using chromatin immunoprecipitation, glutathione-S-transferase pull-down, co-immunoprecipitation, and luciferase assays. m6A levels were determined using m6A dot assay. N6-methyladenosine (m6A) enrichment was determined using methylated RNA immunoprecipitation assay. Cellular functions were determined using Cell Counting Kit-8 assay and propidium iodide staining. Xenograft assay was conducted to further verify the role of PRMT5 in HCC. We found that overexpressed PRMT5 was upregulated in tumor protein p53 (TP53)-mutated HCC patients. TP53 epigenetically in activated PRMT5. PRMT5 deficiency promoted the ferroptosis of HCC cells in vitro and inhibited tumor growth in vivo. Moreover, PRMT5 could interact with RNA binding motif protein 15 (RBM15) to activate ferritinophagy signaling. RBM15-mediated m6A modification of ferritin heavy chain 1 (FTH1), promoting its mRNA expression and stability. However, overexpression of FTH1 suppressed ferroptosis and promoted tumor growth. Taken together, PRMT5/RBM15/ferritinophagy signaling can be a potential target for HCC.