Immunometabolic reprogramming in sepsis: mechanisms, clinical endotypes, and therapeutic opportunities

Abstract

Sepsis, a systemic inflammatory syndrome triggered by infection, is tightly linked to dysregulated host immunometabolism. We review three hallmark metabolic alterations. First, a shift from oxidative phosphorylation (OXPHOS) to glycolysis provides rapid ATP early on; prolonged glycolytic engagement, however, drives excessive cytokine release through abnormal accumulation of metabolic intermediates. Second, impaired fatty acid oxidation (FAO) and disrupted cholesterol homeostasis not only compromise energy supply but also amplify pro-inflammatory signaling. Third, mitochondrial dysfunction unleashes reactive oxygen species (ROS) and derails metabolic homeostasis, promoting multi-organ injury. Notably, short-chain fatty acids (SCFAs) derived from the gut microbiota fine tune pro-versus anti-inflammatory responses via epigenetic regulation of immune cells. We further discuss how metabolic reprogramming governs macrophage polarization and T cell exhaustion, and we summarize therapeutic strategies that target key metabolic nodes. This review provides an integrated perspective on the immunometabolic mechanisms of sepsis and offers a rationale for metabolism-based precision interventions.