METTL3-Mediated N6-Methyladenosine Modification Activates the EGR1-ZBP1 Axis to Promote PANoptosis-Like Cardiomyocyte Death in Myocardial Ischemia-Reperfusion Injury.

Abstract

Myocardial ischemia-reperfusion (I/R) injury is a major cause of cardiac dysfunction, but the mechanisms linking metabolic stress to regulated cardiomyocyte death remain incompletely defined. N6-methyladenosine (m⁶A), the most abundant internal modification of eukaryotic mRNA, is installed by the methyltransferase-like 3 (METTL3)-containing writer complex and regulates RNA fate. Here, we investigated whether METTL3-mediated m⁶A modification contributes to PANoptosis-like cardiomyocyte death during I/R injury. In mouse myocardial I/R and oxygen-glucose deprivation/reoxygenation (OGD/R) models, global m⁶A levels and METTL3 expression were markedly increased. Lactate accumulation was associated with p300-dependent H3K18 lactylation (H3K18la) enrichment at the Mettl3 promoter, suggesting a metabolic-epigenetic mechanism for METTL3 transcriptional upregulation. Functionally, METTL3 promoted PANoptosis-related death signaling, strengthened the association of ZBP1 with PANoptosis-related components, and aggravated infarction, adverse remodeling, and cardiac dysfunction, whereas METTL3 deletion or pharmacological inhibition with STM2457 was protective. Mechanistically, METTL3 enhanced m⁶A modification of Egr1 mRNA, thereby increasing EGR1 expression through YTHDF1-mediated translational regulation and IGF2BP2-mediated mRNA stabilization. EGR1 further activated Zbp1 transcription, and EGR1 restoration partially reversed the protective effects of METTL3 deficiency. These findings identify a lactate-H3K18la-METTL3-EGR1-ZBP1 axis that drives PANoptosis-like cardiomyocyte death and suggest METTL3 inhibition as a potential strategy against I/R-induced cardiac injury.