A Novel Dual Therapy for Diabetic Ischemic Heart Injury: Sinomenine and Liraglutide Restore Mitochondrial Homeostasis and Suppress Pyroptosis

ABSTRACT Type 2 diabetes mellitus (T2DM) significantly amplifies the risk and severity of myocardial ischemia–reperfusion (IR) injury, contributing to the disproportionately high cardiovascular mortality observed in diabetic patients. This study investigated the combined cardioprotective effects of sinomenine and liraglutide in a rat model of T2DM with myocardial IR injury and elucidated the underlying molecular mechanisms. Male Sprague Dawley rats were induced to T2DM with a high‐fat diet and low‐dose streptozotocin. After the induction of diabetes, the rats underwent 30 min of occlusion of the left anterior descending coronary artery, followed by 24 h of reperfusion. Before the IR procedure, diabetic rats were pretreated with sinomenine and/or liraglutide for 7 days. A comprehensive suite of techniques was employed to evaluate various endpoints, including echocardiographic and hemodynamic profiles, infarct size, histopathological alterations, cardiac troponin I (cTn‐I) levels, pyroptosis‐related proteins (NLRP3 and cleaved caspase‐1), mitophagy‐related markers (PINK‐1 and Parkin), oxidative stress indicators (MDA, SOD, and GPx), and pro‐inflammatory cytokines (IL‐18 and IL‐1β). The combination of sinomenine and liraglutide significantly improved cardiac function, reduced infarct size, attenuated histopathological damage, and decreased serum cTn‐I levels ( p < 0.05). It also downregulated the expression of pyroptosis‐related proteins, upregulated the expression of mitophagy‐related proteins, mitigated oxidative stress, and reduced pro‐inflammatory cytokine levels ( p < 0.05). The cardioprotective effects of the combined therapy were largely abrogated by pretreatment with mitochondrial division inhibitor 1. The combination of sinomenine and liraglutide showed remarkable cardioprotective effects against IR injury in diabetic rats, which were associated with the the attenuation of NLRP3‐driven pyroptosis and the enhancement of PINK‐1/Parkin‐mediated mitophagy, suggesting a mechanistic link warranting further validation.