Macrophage metabolic reprogramming: A central hub linking multicellular crosstalk to organ vulnerability in sepsis.

Sepsis is a life-threatening syndrome characterized by dysregulated host responses to infection, often progressing to multiple organ dysfunction syndrome (MODS). Recent evidence highlights macrophage metabolic reprogramming as a critical driver of immune responses, yet macrophages operate within a broader immunometabolic network involving dendritic cells, neutrophils, and lymphocytes that collectively shape sepsis outcomes. The coordination of these metabolic changes across multicellular interactions and their contribution to organ-specific vulnerability remain poorly understood. Here we present a holistic framework linking macrophage metabolism to multicellular communication and organ vulnerability. We discuss how glycolysis, amino acid metabolism, and fatty acid oxidation alter macrophage states via epigenetic and signaling mechanisms, producing metabolites that connect metabolism to inflammation. These signals reshape cellular networks through cytokines, extracellular vesicles, and damage-associated molecule patterns (DAMPs), differentially impacting organs with diverse metabolic demands, including the heart, lung, liver, kidney, brain, and intestine, resulting in distinct injury patterns. Our framework enhances understanding of sepsis-induced organ heterogeneity and advocates for stage-specific, organ-targeted therapies that consider integrated multicellular immunometabolic contributions.