This study investigates the role of the METTL16-SENP3-LTF axis in ferroptosis resistance and hepatocellular carcinoma (HCC) progression. METTL16, an m6A methyltransferase, was identified as a novel ferroptotic repressor in HCC cells. It collaborates with IGF2BP2 to regulate SENP3 mRNA stability through an m6A-dependent mechanism. SENP3, a redox-sensitive SUMO2/3-specific protease, modulates the stability of lactotransferrin (LTF) by de-SUMOylation, which inhibits ferroptosis and promotes HCC development. Elevated LTF expression chelates free iron, reducing the labile iron pool and enhancing ferroptosis resistance. Clinically, high METTL16 and SENP3 expression correlates with poor prognosis in HCC. The METTL16-SENP3-LTF axis is a critical regulator of ferroptosis and HCC progression, and targeting this axis could be a promising strategy for sensitizing ferroptosis and treating HCC. The study provides insights into the molecular mechanisms underlying METTL16's role in HCC and highlights the therapeutic potential of targeting this axis.This study investigates the role of the METTL16-SENP3-LTF axis in ferroptosis resistance and hepatocellular carcinoma (HCC) progression. METTL16, an m6A methyltransferase, was identified as a novel ferroptotic repressor in HCC cells. It collaborates with IGF2BP2 to regulate SENP3 mRNA stability through an m6A-dependent mechanism. SENP3, a redox-sensitive SUMO2/3-specific protease, modulates the stability of lactotransferrin (LTF) by de-SUMOylation, which inhibits ferroptosis and promotes HCC development. Elevated LTF expression chelates free iron, reducing the labile iron pool and enhancing ferroptosis resistance. Clinically, high METTL16 and SENP3 expression correlates with poor prognosis in HCC. The METTL16-SENP3-LTF axis is a critical regulator of ferroptosis and HCC progression, and targeting this axis could be a promising strategy for sensitizing ferroptosis and treating HCC. The study provides insights into the molecular mechanisms underlying METTL16's role in HCC and highlights the therapeutic potential of targeting this axis.