Linnan Li, Jinfeng Gao, Xiaoxue Zhang, Kunming Dai, Hao Cheng, Jianying Ma, Junbo Ge
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.