SiOInduces Iron Overload and Ferroptosis in Cardiomyocytes in a Silicosis Mouse Model.

Abstract

OBJECTIVE: The aim of this study was to explore the role and mechanism of ferroptosis in SiO-induced cardiac injury using a mouse model. METHODS: Male C57BL/6 mice were intratracheally instilled with SiOto create a silicosis model. Ferrostatin-1 (Fer-1) and deferoxamine (DFO) were used to suppress ferroptosis. Serum biomarkers, oxidative stress markers, histopathology, iron content, and the expression of ferroptosis-related proteins were assessed. RESULTS: SiOaltered serum cardiac injury biomarkers, oxidative stress, iron accumulation, and ferroptosis markers in myocardial tissue. Fer-1 and DFO reduced lipid peroxidation and iron overload, and alleviated SiO-induced mitochondrial damage and myocardial injury. SiOinhibited Nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant genes, while Fer-1 more potently reactivated Nrf2 compared to DFO. CONCLUSION: Iron overload-induced ferroptosis contributes to SiO-induced cardiac injury. Targeting ferroptosis by reducing iron accumulation or inhibiting lipid peroxidation protects against SiOcardiotoxicity, potentiallymodulation of the Nrf2 pathway.