Integrating immunometabolic reprogramming and regulated cell death pathways in sepsis-induced myocardial dysfunction

Abstract

Sepsis-induced myocardial dysfunction contributes substantially to mortality in critically ill patients, yet mechanistically targeted therapies remain limited. Macrophage immunometabolic reprogramming has been proposed as a candidate link between systemic inflammatory cascades and cardiomyocyte energetic collapse, but this axis remains insufficiently integrated into clinical frameworks, and most supporting evidence is preclinical. This narrative review synthesizes mechanistic, translational, and therapeutic evidence on the macrophage immunometabolic shifts that may connect the systemic cytokine storm to cardiomyocyte energy failure during sepsis, and appraises the provenance, hierarchy, and translational readiness of this evidence for precision-stratified critical care. We examine macrophage metabolic reprogramming from oxidative phosphorylation toward glycolytic flux, its modulation by hypoxia signaling, lactate-driven histone lactylation, and the sequestration of tricarboxylic acid cycle intermediates that sustain inflammatory phenotypes. We integrate these shifts with cardiomyocyte mitochondrial dysfunction, activation of the nucleotide-binding, leucine-rich repeat, and pyrin domain-containing 3 inflammasome, mitochondrial dynamics disruption, and regulated cell death pathways including ferroptosis and cuproptosis. The gut-heart and gut-lung axes are appraised as remote immunometabolic inputs, cardiorenal cross-talk is incorporated, and biomarker and machine-learning endotyping strategies are evaluated for their capacity to stratify patients for immunomodulatory intervention. Macrophage immunometabolic reprogramming constitutes a plausible, predominantly preclinical bridge between systemic cytokine storm and cardiomyocyte energy failure in sepsis, offering therapeutic targets that require prospective validation across precision-stratified populations. Macrophages switch to glycolysis during sepsis, fueling inflammation that strains the failing heart. Lactate-driven epigenetic changes lock macrophages into a state that deepens cardiomyocyte energy failure. Targeting immunometabolism and regulated cell death offers new ways to protect the septic heart.