Seipin‐Mediated Lipid Droplet Formation in Cardiomyocytes Ameliorates Cardiac Ischemia/Reperfusion Injury

Cardiac ischemia/reperfusion (I/R) injury is an important therapeutic target for ischemic heart disease. Lipid droplets (LDs) are the key organelles involved in lipid metabolism. This study aimed to identify the LD‐mediated protection against lipotoxicity in cardiac I/R injury. LD accumulation is upregulated in hearts subjected to I/R injury; however, it is insufficient to neutralize lipotoxicity or prevent cardiomyocyte death. Seipin played a central role in LD biogenesis in cardiomyocytes following I/R injury. Seipin deficiency led to reduced LD levels and exacerbated cardiac I/R injury. Whereas increased LD levels, via Seipin overexpression or lipolysis inhibition, ameliorated myocardial I/R injury. I/R‐induced downregulation of Seipin is attributed to the reduced expression of its transcription factor USF1, which is required for metabolic adaptation in acute myocardial ischemia. These findings not only elucidate the pathophysiological roles of LDs and Seipin but also provide a promising therapeutic target for myocardial I/R injury.