HERC2 as a bidirectional iron metabolism switch: Synergistic NCOA4 stabilization and FBXL5 degradation drive ferroptosis-cascaded hepatotoxicity in Nd2O3 nanoparticles exposure.

Neodymium oxide nanoparticles (NdNPs), pivotal materials in advanced manufacturing and frontier technologies, raise growing concerns due to their potential risk to environment and health risks. Epidemiological studies linked neodymium exposure to liver dysfunction, but the underlying mechanisms remained unclear. Here, we demonstrated that respiratory exposure to NdNPs led to significant hepatic accumulation, second only to the lungs, and induced liver injury in mice, characterized by increased parenchymal echogenicity, histopathological and ultrastructural damage, and hepatocyte ferroptosis. In HepG2 cells, NdNPs triggered ferroptosis, as evidenced by reduced cell viability, mitochondrial membrane/cristae disruption, elevated redox-active iron, exacerbated lipid peroxidation, and impaired repair capacity. The ferroptosis inhibitors ferrostatin-1 (Fer-1) and deferoxamine (DFO) rescued NdNPs-induced cell death, confirming ferroptosis. Mechanistically, NdNPs dysregulated iron homeostasis through dual HERC2-mediated pathways: (i) weakening HERC2-NCOA4 binding stabilized NCOA4, enhancing ferritinophagy-mediated redox-active iron release; and (ii) strengthening HERC2-FBXL5 interaction promoted FBXL5 degradation, derepressing IRP2/TFR1-mediated redox-active iron uptake. Together, these actions synergistically expanded the labile iron pool, driving lethal lipid peroxidation and ferroptosis. Critically, NCOA4 knockout, inhibition of the HERC2-FBXL5 interaction, and FBXL5 overexpression each significantly alleviated NdNPs-induced elevation of redox-active iron, lipid peroxidation, impairment of lipid peroxidation repair capacity, and cell death. Our findings establish HERC2-mediated dual-axis iron dysregulation as a previously unrecognized driver of NdNPs hepatotoxicity.