Iron-bearing nanoparticles trigger human umbilical vein endothelial cells ferroptotic responses by promoting...

Iron-bearing nanoparticles (IBNPs) were abundant in particulate matter (PM). Due to their high reactivity, IBNPs were considered hazardous to human health, however, their toxic mode-of-action(s) are highly unclear. Ferroptosis is a novel programmed cell death (PCD) that highly associated with intracellular iron. However, the pro-ferroptotic effect of IBNPs has not been characterized. To this end, we ought to investigate whether and how IBNPs (synthetic γ-Fe₂O₃ and Fe₃O₄ NPs were selected as the model compounds) are involved in ferroptosis. We found that human umbilical vein endothelial cells (HUVECs) phagocytized large qualities of γ-Fe₂O₃ and Fe₃O₄ NPs, resulting in increased intracellular iron level. We further observed the disrupted cystine/glutamate reverse transporter (System X_c^-) and glutathione peroxidase 4 (GPX4) signaling in γ-Fe₂O₃ and Fe₃O₄ NPs-challenged HUVECs. γ-Fe₂O₃ and Fe₃O₄ NPs could also cause mitochondrial fusion and fission dysregulation, activate lipid peroxidation and iron metabolism-related genes in a P53-dependent manner. Together, the ferroptotic activity of IBNPs should be acknowledged for the risk assessment of PM associated health effects.