METTL3-mediated m6A modification of FDX1 confers resistance to cuproptosis and promotes hepatocellular carcinoma progression.

Cuproptosis, a copper-dependent cell death pathway, is emerging as a potential cancer treatment strategy. N6-methyladenosine (m6A), the predominant eukaryotic RNA modification, regulates various cell death mechanisms; however, its role in cuproptosis within hepatocellular carcinoma (HCC) remains unclear. Here, we found that METTL3 expression and m6A modification are upregulated during cuproptosis in HCC cells. Mechanistically, METTL3 mediated m6A modification of FDX1 mRNA, whereas the m6A reader FMR1 inhibited FDX1 translation. Consequently, METTL3 conferred resistance to cuproptosis by suppressing FDX1 protein expression in an m6A-FMR1-dependent manner. Knockdown or pharmacological inhibition of METTL3 sensitized HCC cells to elesclomol-Cu-induced cuproptosis and effectively suppressed HCC xenograft growth in vivo. Clinically, elevated METTL3 expression was associated with poor HCC prognosis, and the protein expression of METTL3 and FDX1 was negatively correlated in HCC tissues. In conclusion, our findings identify an METTL3-mediated m6A regulatory mechanism controlling cuproptosis sensitivity, revealing METTL3 inhibition as a promising therapeutic strategy for HCC.