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

<i>In vivo</i>, 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. <i>In vitro</i>, 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 pyroptosis <i>via</i> the m6A/IGF2BP1-NLRP3 axis, providing a novel epitranscriptomic mechanism for cardioprotection against MIRI. <i>Antioxid. Redox Signal.</i> 44, 103-117.