Silica nanoparticles induce ferroptosis of HUVECs by triggering NCOA4-mediated ferritinophagy.

Silica nanoparticles (SiNPs) have been widely used in electronics, chemistry, and biomedicine. Human exposure to SiNPs and possible health effects have attracted much attention. The potential cardiovascular toxicity of SiNPs and their related mechanisms are still unclear. Therefore, in this study, we investigated the toxic effects of SiNPs on human umbilical vein endothelial cells (HUVECs). We found that SiNPs could induce HUVECs ferroptosis. The results showed that the level of intracellular divalent iron and lipid peroxidation increased, and mitochondrial cristae decreased. In addition, the pretreatment of the iron chelator deferoxamine mesylate (DFO) could alleviate the ferroptosis of cells. Interestingly, pretreatment of 3-methyladenine (3-MA), an autophagy/PI3K inhibitor could partially inhibit autophagy and reduce ferroptosis, which indicated that autophagy played an important role in cell ferroptosis. Additionally, after knocking down nuclear receptor coactivator 4 (NCOA4), Ferritin Heavy Chain 1 (FTH1) expression was up-regulated, and the levels of divalent iron and lipid peroxidation decreased, which suggested that NCOA4 mediated the ferroptosis of HUVECs induced by SiNPs. In conclusion, this study shows that SiNPs can induce cardiovascular toxicity in which there is ferroptosis. NCOA4-mediated ferritinophagy and resultant ferroptosis by SiNPs may play an important role. This study provides a new theoretical strategy for the treatment and prevention of cardiovascular diseases in the future.