The immunometabolic axis of sepsis-related myocardial injury: macrophage reprogramming as a central mechanism and therapeutic target

Sepsis-related myocardial injury (SRMI) is a major cause of death in critically ill patients, with pathogenesis extending beyond inflammation to encompass dysregulated immunometabolic crosstalk. This review elucidates macrophage metabolic reprogramming as a central mechanism driving SRMI, detailing how a shift to aerobic glycolysis fuels pro-inflammatory responses, while oxidative phosphorylation supports reparative functions. We emphasize that metabolites like succinate, itaconate, and lactate act as potent signaling molecules, orchestrating epigenetic changes and inflammatory pathways. Furthermore, we deconstruct the critical immunometabolic dialogue mediated by extracellular vesicles (EVs) and signaling cascades among macrophages, cardiomyocytes, and endothelial cells. Translating these insights, we evaluate next-generation therapeutic strategies aimed at this immunometabolic axis, including precision small-molecule modulators, nucleic acid-based technologies, and biologics. These approaches represent a promising strategic shift from non-specific immunosuppression toward targeted immunometabolic modulation. This synthesis provides a foundational framework for understanding SRMI and charts a roadmap for developing novel precision medicine interventions to improve patient outcomes.