m6A RNA methylation in sepsis-induced cardiomyopathy: direct cardiac mechanisms, emerging therapeutic targets, and translational gaps.

Sepsis-induced cardiomyopathy (SICM) develops in up to 60% of patients with sepsis, substantially increases mortality, and currently lacks specific pharmacotherapy. N6-methyladenosine (m6A), the most prevalent internal modification on eukaryotic mRNA, dynamically regulates transcript fate through coordinated actions of methyltransferases (writers), demethylases (erasers), and binding proteins (readers). Direct cardiac studies have now implicated multiple m6A regulators in several key cellular processes relevant to SICM, including inflammatory injury, apoptosis, pyroptosis, ferroptosis, and adaptive mitophagy. Current evidence highlights pronounced context dependence: the eraser FTO shows the most consistent cardioprotective profile across inflammation, ferroptosis, and mitophagy, whereas the other eraser ALKBH5 paradoxically promotes pyroptotic injury, and the writer METTL3 predominantly drives damage through distinct transcript-reader axes. Notably, several independent m6A pathways converge on the SLC7A11/GPX4/NRF2 antioxidant network, suggesting that ferroptosis-centered m6A regulation may represent the most coherent translational entry point identified thus far. This review synthesizes the direct cardiac evidence using a process-oriented framework, distinguishes injury-associated pathways from adaptive mitochondrial quality control, and identifies critical translational gaps-including heavy reliance on lipopolysaccharide-based models, limited use of primary cardiomyocytes and cardiac-specific genetic tools, and the absence of human validation-that must be addressed before m6A-targeted strategies can advance toward clinical application.