Silica nanoparticles induce liver lipid metabolism disorder via ACSL4-mediated ferroptosis

The disease burden of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. Emerging evidence has revealed that silica nanoparticles (SiNPs) could disorder the liver lipid metabolism and cause hepatotoxicity, but the underlying mechanism remains unknown. The purpose of this study is to elucidate the molecular mechanism of hepatic lipid metabolism disorder caused by SiNPs, and to reveal the role of ferroptosis in SiNPs-induced hepatotoxicity. To explore the phenotypic changes in liver, the wild-type C57BL/6J mice were exposed to different doses of SiNPs (5, 10, 20 mg/kg·bw) with or without melatonin (20 mg/kg·bw). SiNPs accelerated hepatic oxidative stress and promoted pathological injury and lipid accumulation, resulting in NAFLD development. Melatonin significantly inhibited the oxidative damage caused by SiNPs. Then, the hepatocytes were treated with SiNPs, the ferroptosis inducer and inhibitor, respectively. In vitro, SiNPs (25 μg/mL) generated mitochondrial and intracellular Fe