Abstract
Ferroptosis is a reactive oxygen species (ROS)- and iron-dependent form of regulated cell death (RCD), playing critical roles in organ injury and targeting therapy of cancers. Previous studies have demonstrated that ferroptosis participates in the development of cardiomyopathy including cardiac hypertrophy, diabetic cardiomyopathy and doxorubicin-induced cardiotoxicity. However, the role of ferroptosis in sepsis-induced cardiac injury remains unclear. This study aimed to explore the role and underlying mechanism of ferroptosis on lipopolysaccharide (LPS)-induced cardiac injury. Mice were injected with LPS (10 mg/kg) for 12 h to generate experimental sepsis. Ferrostatin-1 (Fer-1) and Dexrazoxane (DXZ) were used to suppress ferroptosis of mice with sepsis-induced cardiac injury. LPS increased the levels of ferroptotic markers involving prostaglandin endoperoxide synthase 2 (PTGS2), malonaldehyde (MDA) and lipid ROS, apart from resulting in obvious mitochondria damage, which were alleviated by Fer-1 and DXZ. In vitro experiments showed that Fer-1 inhibited LPS-induced lipid peroxidation and injury of H9c2 myofibroblasts while erastin and sorafenib aggravated LPS-induced ferroptosis. Additionally, Fer-1 and DXZ improved survival rate and cardiac function of mice with sepsis. Mechanistically, LPS increased the expression of nuclear receptor coactivator 4 (NCOA4) and the level of intracellular Fe2+ but decreased the level of ferritin. NCOA4 could directly interact with ferritin and degrade it in a ferritinophagy-dependent manner, which subsequently released a great amount of iron. Cytoplasmic Fe2+ further activated the expression of siderofexin (SFXN1) on mitochondrial membrane, which in turn transported cytoplasmic Fe2+ into mitochondria, giving rise to the production of mitochondrial ROS and ferroptosis. Based on these findings, we concluded that ferritinophagy-mediated ferroptosis is one of the critical mechanisms contributing to sepsis-induced cardiac injury. Targeting ferroptosis in cardiomyocytes may be a therapeutic strategy for preventing sepsis in the future.