Metformin Protects Against Myocardial Ischemia/Reperfusion Injury and Suppresses the Nur77-SPARCL1 Inflammatory Axis

Myocardial ischemia/reperfusion (I/R) injury triggers sterile inflammation that amplifies tissue damage. We investigated whether metformin limits this response through the Nur77-SPARCL1 axis. RNA sequencing of HL-1 cardiomyocytes (n = 3 biological replicates per group) identified Sparcl1 as a metformin-responsive transcript. Mechanistically, metformin reduced Nur77 and SPARCL1 expression, while Nur77 directly bound the Sparcl1 promoter and activated transcription in a binding-site-dependent manner. Sparcl1 silencing in cardiomyocytes reduced the expression and secretion of pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β) following hypoxia/reoxygenation. In vivo, using a mouse I/R model (n = 5 mice per group), Sparcl1 knockdown protected against myocardial injury by reducing infarct size, improving left ventricular function, and shifting the myocardial environment toward a reparative state-evidenced by increased ARG1- and CD206-positive cells, and reduced CD86- and iNOS-positive cells alongside lowered inflammatory cytokines. Furthermore, Nur77 overexpression alone aggravated I/R injury, increasing SPARCL1 expression, infarct size, and pro-inflammatory macrophage markers while impairing cardiac function and reducing AMPK/ACC phosphorylation. Metformin partially opposed these detrimental effects in Nur77-overexpressing mice. Together, these findings support the involvement of a Nur77-SPARCL1 inflammatory axis in myocardial I/R injury and in metformin-associated cardioprotection, while not excluding parallel Nur77-independent or AMPK-dependent mechanisms.