NF-κB signaling as a central integrator of inflammation, stress-induced metabolic dysfunction, and cardiomyocyte fate in sepsis-induced myocardial injury

Sepsis-induced myocardial injury is a frequent and life-threatening complication of sepsis, characterized by transient yet profound cardiac dysfunction that markedly worsens patient outcomes. Despite extensive investigation, the molecular mechanisms linking systemic inflammation to myocardial metabolic failure and cardiomyocyte loss remain incompletely understood. Emerging evidence indicates that nuclear factor-κB (NF-κB) signaling functions as more than a canonical inflammatory pathway in this context. In this review, we propose a unifying framework in which NF-κB serves as a central integrator linking inflammatory stress, stress-induced metabolic dysfunction, and cardiomyocyte fate in sepsis-induced myocardial injury. We summarize how NF-κB-driven inflammatory amplification, through crosstalk with MAPK signaling and immune cell activation, reshapes the myocardial immune microenvironment. We further discuss how NF-κB interfaces with oxidative stress, mitochondrial dysfunction, redox imbalance, and ferroptosis-related metabolic stress, thereby disrupting cardiomyocyte homeostasis. Importantly, NF-κB is highlighted as a context-dependent determinant of cardiomyocyte fate, modulating apoptosis, pyroptosis, and non-apoptotic cell death programs under septic conditions. Finally, we discuss emerging NF-κB-directed therapies and the need for tissue-specific combination strategies. This integrative framework may guide more precise therapeutic development for sepsis-induced myocardial injury.