Obesity-associated Metabolic Dysregulation Aggravates Myocardial Ischemia-Reperfusion Injury through Gls2-Mediated Ferroptosis

Metabolic diseases, including obesity, are becoming increasingly prevalent worldwide. However, the extent to which obesity-associated metabolic dysregulation exacerbates myocardial ischemia-reperfusion (IR) injury, and its specific impact on the patterns of cell death in this context, remain insufficiently understood. In this study, we demonstrate that obesity-associated metabolic dysregulation leads to more severe cardiac IR injury. This effect is not due to increased IR-mediated myocardial apoptosis, but rather to enhanced IR-induced ferroptosis. Our findings indicate that obesity-associated metabolic dysregulation aggravates cardiac ferroptosis primarily by upregulating glutaminase 2 (Gls2) expression in the heart. Furthermore, inhibition of Gls2 may attenuate IR injury exacerbated by obesity-associated metabolic dysregulation. • Obesity-associated metabolic dysregulation aggravated the injury of cardiac IR. • Obesity-associated metabolic dysregulation enhanced injury through increased ferroptosis. • Elevated Gls2 expression contributed to intensive ferroptosis.