METTL16-mediated m6A modification regulates SENP3-LTF axis and ferroptosis in Nd(NO₃)₃-induced hepatotoxicity.

Neodymium (Nd), a widely used rare earth element, poses potential health risks, though its toxic mechanisms remain incompletely understood. This study investigated the role of ferroptosis in Nd(NO₃)₃-induced hepatotoxicity and the regulatory function of the METTL16-SENP3-LTF axis. In vitro, AML12 cells exposed to Nd(NO₃)₃ (0, 0.8 μM, 24 h) showed dose-dependent downregulation of GPX4 (P < 0.01), upregulation of ACSL4 (P < 0.001), increased lipid peroxidation (evidenced by elevated MDA and enhanced C11-BODIPY oxidation, both P < 0.0001), elevated ROS (P < 0.01), and depleted GSH (P < 0.01). In vivo, C57BL/6 J mice orally administered Nd(NO₃)₃ (55 mg/kg, 6 months) exhibited similar ferroptotic markers. METTL16 knockdown enhanced ferroptosis sensitivity, with increased SENP3 and LTF mRNA and protein expression (P < 0.0001), elevated intracellular free iron, and higher cell mortality. Molecular docking predicted, and MeRIP-seq experimentally validated, METTL16-dependent m⁶A modification on SENP3 mRNA, which stabilizes its expression and promotes LTF-mediated iron accumulation. These findings reveal that Nd(NO₃)₃ triggers hepatocyte ferroptosis via METTL16-SENP3-LTF axis dysregulation, providing new insights into Nd toxicity mechanisms.