Redox-sensitive m6A regulation in atherosclerosis: METTL3 at the crossroads of mitochondrial quality control and pyroptosis

N⁶-methyladenosine (m⁶A) RNA methylation, primarily mediated by methyltransferase-like 3 (METTL3), has emerged as a redox-sensitive epitranscriptomic switch in atherosclerosis (AS). Oxidative stress (OS) remodels the vascular transcriptome via m⁶A reprogramming, driving endothelial dysfunction, vascular smooth muscle cell (VSMC) phenotypic transition, and macrophage inflammatory activation. Reactive oxygen species directly influence METTL3 expression and activity, while METTL3 reciprocally modulates oxidative stress by regulating antioxidant defenses, ROS-scavenging enzymes, and redox homeostasis. Mechanistically, METTL3 promotes mitochondrial fission by enhancing Drp1 translation and suppresses mitochondrial biogenesis via destabilizing PGC-1α transcripts, converging to impair redox resilience and amplify inflammation. Inhibition of METTL3 alleviates intimal hyperplasia, restores contractile phenotypes, and may synergize with antioxidant therapy, mitochondrial quality control reinforcement, or pyroptosis suppression. Beyond METTL3, METTL4-mediated mitochondrial DNA 6 mA methylation also contributes to AS, with selective antagonists providing vascular protection. Natural products such as tanshinone and quercetin modulate m⁶A pathways, offering molecularly defined yet culturally rooted interventions. Deciphering the bidirectional crosstalk between ROS and epitranscriptomic regulation will guide precision therapeutics that bridge oxidative biology, RNA regulation, and translational cardiovascular medicine.