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 both in vivo and in vitro models.

Results:

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