Dapagliflozin attenuates LPS-induced myocardial injury by reducing ferroptosis

Abstract Lipopolysaccharide induces sepsis in vivo, with a significant proportion of septic patients progressing to septic cardiomyopathy. Previous studies have reported the involvement of ferroptosis in the pathogenesis of septic cardiomyopathy. SGLT2 inhibitors such as dapagliflozin have been demonstrated to have cardioprotective effects, with reports indicating a reduction in myocardial ischemia-reperfusion injury through the attenuation of ferroptosis. However, the role of ferroptosis-induced myocardial injury in the context of LPS-induced sepsis remains unclear. Therefore, our study aims to investigate the therapeutic effects of dapagliflozin on LPS-induced iron-overload cardiac injury. Our results indicate that dapagliflozin inhibits the translation of key proteins associated with ferroptosis, including GPX4, FTH1, and SLC7A11, while reducing the transcription of lipid peroxidation-related mRNAs PTGS2 and ACSL4, as well as iron metabolism genes TFRC and HMOX1. Additionally, both compounds alleviate potential mitochondrial membrane damage. Furthermore, dapagliflozin has been shown to mitigate LPS-induced cardiac injury burden. Based on these findings, we conclude that dapagliflozin can alleviate LPS-induced iron dysregulation-mediated cardiac dysfunction, expanding the clinical indications for SGLT2 inhibitors.