Involvement of ferroptosis in methymercury-induced neurotoxicity in SH-SY5Y neuroblastoma cell

Methylmercury (MeHg) exposure represents a significant threat to the nervous system, yet the potential induction of ferroptosis in neuronal cells by MeHg has been scarcely investigated. This study was designed to comprehensively explore the MeHg-triggered ferroptosis in SH-SY5Y neuroblastoma cells. Through microscopic observation, significant morphological changes in mitochondria were noted, including shrinkage and loss of cristae. Biochemically, MeHg exposure induced a significant increase in lipid peroxidation, as evidenced by elevated malondialdehyde (MDA) levels (reaching up to 19.03-fold of the control) and enhanced fluorescence of the lipid ROS probe BODIPY™ 581/591 C11 (up to 5.49-fold) following 24-h exposure to 8 μM MeHg. Furthermore, MeHg triggered intracellular iron overload, with levels increasing by up to 1.42-fold of control. Concurrently, the expression of GPX4, NRF2, and FTH1 was downregulated, while TFRC expression was upregulated. Notably, the ferroptosis inhibitor ferrostatin-1 (Fer-1) and iron chelator deferoxamine (DFO) could partially reverse these MeHg-induced alterations. These findings strongly suggest that MeHg-induced ferroptosis in SH-SY5Y cells is closely associated with iron overload, lipid peroxidation, and the disruption of antioxidant pathways, thus providing novel insights into the complex mechanisms of MeHg-induced neurotoxicity.