Sestrin2 ameliorates LPS-induced cardiomyocyte injury by inhibiting ferroptosis via the Nrf2/HO-1 pathway.

BACKGROUND: The pathogenesis of sepsis-induced myocardial injury is complex. Currently, treatment for this disease remains suboptimal. Sestrin2 (Sesn2) is an antioxidant protein and has been shown to have a protective role in some diseases. However, its role in sepsis-induced cardiomyocyte injury has not been fully elucidated. METHODS: An in vitro model of sepsis-induced myocardial injury was established by treating H9c2 cardiomyocytes with lipopolysaccharide (LPS). The viability of H9c2 cardiomyocytes was quantified using the cell counting kit-8. Protein expression levels were analyzed by Western blotting. Apoptosis and mitochondrial membrane potential were quantified by flow cytometry. Mitochondrial ultrastructure was observed by transmission electron microscopy. Malondialdehyde (MDA), superoxide dismutase (SOD), reduced glutathione (GSH), reactive oxygen species (ROS), and iron content were quantified using commercial assay kits. The ferroptosis inducer Erastin was employed to further investigate the role of Sesn2 in ferroptosis. The potential regulatory relationship between Sesn2 and the Nrf2/HO-1 pathway was investigated using the Nrf2 inhibitor ML385. RESULTS: Sesn2 overexpression significantly improved cell viability, ameliorated mitochondrial damage, upregulated GPX4 and SLC7A11 expression, downregulated ACSL4 expression, reduced MDA and Fe(2)⁺ levels, elevated SOD activity and GSH content, and attenuated ROS accumulation in LPS-induced H9c2 cardiomyocytes. Sesn2 overexpression significantly suppresses apoptosis. Furthermore, Sesn2 overexpression can activate the Nrf2/HO-1 pathway. Both Erastin and ML385 reversed Sesn2 overexpression-mediated regulation of ferroptosis-associated proteins in LPS-treated H9c2 cells. CONCLUSIONS: This study demonstrates that Sesn2 inhibits ferroptosis in LPS-treated H9c2 cells through the Nrf2/HO-1 pathway, and also exerts an anti-apoptotic effect.