Silica nanoparticles induce hepatocyte ferroptosis and liver injury via ferritinophagy

Abstract

As one of the most mass-produced and extensively used engineered nanomaterials, silica nanoparticles (SiNPs) have gained attention due to their environmental health and safety (EHS) concerns because of the increasing exposure hazards to environment and human beings. SiNPs have been reported to induce liver toxicity, but its potential mechanism has not been fully clarified. The purpose of this study was to investigate whether SiNPs caused hepatocyte ferroptosis and liver injury via ferritinophagy. In the in vivo study, SiNPs led to histopathological damage in liver, accompanied by hepatocellular ferroptosis, which was characterized by lipid peroxidation and ferritinophagy. In vitro, SiNPs could trigger ferroptosis in L-02 cells, as evidenced by the cell viability reduction, mitochondrial membrane/cristae rupture, phospholipid hydroperoxides (PL-OOH) aggravation, mitochondrial/intracellular free ferrous iron accumulation, and lipid peroxidation repair capacity impairment. Importantly, ferrostatin-1 (Fer-1) rescued the SiNP-induced cytotoxiciy and lipid peroxidation. Further, SiNPs caused the complete ferritinophagy process from autophagosomes containing ferritin formation to degradation. Notably, bafilomycin A1 (BafA1) caused the further accumulation of autophagosomes containing ferritin induced by SiNPs. Interestingly, NCOA4 knockdown inhibited the degradation of ferritin, reduced the intracellular free ferrous iron, alleviated lipid peroxidation and its repair capacity impairment, and finally decreased SiNP-caused cell death. In addition, the ratio of autophagosome accumulation caused by the inhibition of ferritinophagy to autophagy was estimated to be 53%. In summary, our data suggested that NCOA4-mediated ferritinophagy, as an important form of autophagy induced by SiNPs, was a novel mechanism for SiNP-motivated hepatocyte ferroptosis and liver injury, which was reported for the first time.