This study investigates the role of the METTL16-SENP3-LTF axis in ferroptosis and hepatocellular carcinoma (HCC). METTL16, an m6A methyltransferase, was identified as a novel repressor of ferroptosis in HCC cells. High METTL16 expression confers ferroptosis resistance and promotes cell viability and tumor progression. Mechanistically, METTL16 collaborates with IGF2BP2 to modulate SENP3 mRNA stability in an m6A-dependent manner. SENP3 then impairs the proteasome-mediated ubiquitination degradation of Lactotransferrin (LTF) via de-SUMOylation. Elevated LTF expression facilitates iron chelation and reduces the labile iron pool level. In vivo and in vitro studies, as well as clinical data, support the clinical significance of this axis. Targeting this axis is proposed as a promising strategy to sensitize ferroptosis and combat HCC.This study investigates the role of the METTL16-SENP3-LTF axis in ferroptosis and hepatocellular carcinoma (HCC). METTL16, an m6A methyltransferase, was identified as a novel repressor of ferroptosis in HCC cells. High METTL16 expression confers ferroptosis resistance and promotes cell viability and tumor progression. Mechanistically, METTL16 collaborates with IGF2BP2 to modulate SENP3 mRNA stability in an m6A-dependent manner. SENP3 then impairs the proteasome-mediated ubiquitination degradation of Lactotransferrin (LTF) via de-SUMOylation. Elevated LTF expression facilitates iron chelation and reduces the labile iron pool level. In vivo and in vitro studies, as well as clinical data, support the clinical significance of this axis. Targeting this axis is proposed as a promising strategy to sensitize ferroptosis and combat HCC.