3'-Methoxypuerarin Ameliorates Myocardial Ischemia/Reperfusion-Induced Pyroptosis via Regulating IGF2BP1/m6A/NLRP3 Pathway.

Abstract

AIMS: This study aimed to investigate the protective effects of 3'-Methoxypuerarin (3'-MOP) on myocardial ischemia-reperfusion injury (MIRI) and elucidate its underlying mechanisms. Specifically, we examined its role in modulating N6-methyladenosine (m6A) methylation and suppressing cardiomyocyte pyroptosis in bothandmodels. RESULTS: , treatment with 3'-MOP markedly reduced myocardial infarct size, preserved cardiac function, and alleviated histopathological injury following ischemia/reperfusion. Consistently, 3'-MOP suppressed m6A methylation and significantly decreased the expression of pyroptosis-related proteins, including NLRP3, cleaved GSDMD, cleaved Caspase-1, IL-1β, and IL-18., 3'-MOP decreased m6A methylation, destabilized NLRP3 mRNA, and inhibited pyroptosis in hypoxia/reoxygenation-induced cardiomyocytes. Mechanistically, 3'-MOP disrupted the interaction between insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1) and NLRP3 mRNA, regulated m6A modification at predicted NLRP3 sites, and promoted mRNA degradation, thereby mimicking the effects of si-IGF2BP1 and attenuating pyroptottenuating pyroptosis.Conclusion and Innovation:3'-MOP exerts cardioprotective effects against MIRI by modulating m6A methylation and inhibiting pyroptosis. This study is the first to demonstrate that 3'-MOP regulates cardiomyocyte pyroptosisthe m6A/IGF2BP1-NLRP3 axis, providing a novel epitranscriptomic mechanism for cardioprotection against MIRI.44, 103-117.