m6A epitranscriptomic remodeling links redox stress to mitochondrial quality control and programmed cell death in sepsis-induced myocardial dysfunction

Sepsis-induced myocardial dysfunction (SIMD) is a major contributor to sepsis-related mortality and is characterized by excessive oxidative stress, mitochondrial dysfunction, and heterogeneous forms of programmed cell death. However, how cardiomyocytes interpret redox stress and commit to distinct death pathways remains incompletely understood. Increasing evidence suggests that N 6 -methyladenosine (m 6 A), the most abundant internal RNA modification, functions as a dynamic post-transcriptional regulator linking redox signaling to mitochondrial homeostasis and cell fate decisions. This review summarizes recent advances indicating that m 6 A-dependent regulatory networks integrate mitochondrial reactive oxygen species (mtROS), mitochondrial quality control (MQC), and downstream cell death pathways in SIMD. Under septic conditions, sustained inflammation and oxidative stress perturb the balance of m 6 A writers, erasers, and readers, leading to maladaptive remodeling of mitochondrial dynamics, mitophagy, and biogenesis. Such epitranscriptomic dysregulation is associated with mtROS accumulation, impaired mitochondrial renewal, and a shift from adaptive redox compensation toward irreversible cardiomyocyte injury. Importantly, emerging evidence suggests that m 6 A remodeling does not uniformly activate cell death but modulates redox signal processing in a context-dependent manner. Preferential amplification of inflammatory sensing and inflammasome signaling may bias mtROS toward pyroptotic execution, whereas compromised antioxidant capacity, iron handling, and lipid metabolism may increase vulnerability to ferroptosis. On this basis, we propose the m 6 A–ROS–MQC axis as a unifying, hypothesis-driven framework for understanding SIMD pathogenesis, in which m 6 A acts as a redox-responsive epitranscriptomic regulator coordinating mitochondrial adaptation and programmed cell death decisions.