Abstract

Aims To elucidate the cardioprotective effect of sinomenine (SIN) against myocardial ischemia/reperfusion injury (MIRI) and to investigate the role of the α7 nicotinic acetylcholine receptor (α7nAChR) and its downstream mechanisms. Materials and methods A murine MIRI model and cardiomyocyte hypoxia/reoxygenation (H/R) models were employed. Key parameters measured included myocardial infarct size, cardiac function, lactate dehydrogenase (LDH) activity, cell viability, adenosine triphosphate (ATP) content, 4-hydroxynonenal (4-HNE) level, α7nAChR expression, mitochondrial reactive oxygen species (ROS), and markers of PANoptosis and ferroptosis. The role of α7nAChR was verified using its antagonist methyllycaconitine and specific siRNA. The mitochondrial antioxidant mito-TEMPO served as a positive control in key cellular assays. Key findings SIN reduced myocardial infarct size, serum LDH, and cardiomyocyte apoptosis, while improving cardiac function and increasing myocardial ATP and α7nAChR expression in MIRI mice, with concordant reductions in oxidative stress marker 4-HNE. In H/R-injured cardiomyocytes, SIN restored cell viability, decreased LDH release, preserved ATP, attenuated oxidative stress (4-HNE, mitochondrial ROS), and upregulated α7nAChR. SIN concurrently suppressed PANoptosis (apoptosis, necroptosis, pyroptosis) and ferroptosis. The efficacy of SIN in reducing mitochondrial ROS and cell death was comparable to mito-TEMPO. All protective effects of SIN were abolished by inhibition of α7nAChR. Significance This study provides the first evidence linking SIN's cardioprotection to the concurrent inhibition of PANoptosis and ferroptosis via α7nAChR activation. We demonstrate that SIN protects against MIRI by activating α7nAChR, thereby improving mitochondrial function, reducing oxidative stress, and suppressing integrated cell death pathways, identifying α7nAChR as a promising target for MIRI.