m⁶A epitranscriptomic remodeling links redox stress to mitochondrial quality control and programmed cell death in...

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 N⁶-methyladenosine (m⁶A), 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 m⁶A-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 m⁶A 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 m⁶A 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 m⁶A-ROS-MQC axis as a unifying, hypothesis-driven framework for understanding SIMD pathogenesis, in which m⁶A acts as a redox-responsive epitranscriptomic regulator coordinating mitochondrial adaptation and programmed cell death decisions.