METTL3介导的N6-甲基腺苷修饰激活EGR1-ZBP1轴，促进心肌缺血再灌注损伤中类似PANoptosis的心肌细胞死亡

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 (m 6 A), 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 m 6 A 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 m 6 A 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 m 6 A 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. Myocardial ischemia‐reperfusion injury promotes lactate accumulation and H3K18 lactylation at the Mettl3 promoter, inducing METTL3 expression in cardiomyocytes. METTL3 installs m 6 A on Egr1 mRNA, enhancing EGR1 expression via YTHDF1‐mediated translation and IGF2BP2‐dependent stabilization. EGR1 ac