The Immunometabolic Architecture of Sepsis: Bridging Cellular Bioenergetics and Systemic Immune Dysregulation

Sepsis continues to be a leading public health challenge, accounting for almost 20% of annual global deaths. Here, we review the evolving pathophysiological understanding of this syndrome by highlighting the central role of immunometabolism. We move beyond the biphasic model to argue that hyperinflammation and immunosuppression coexist across different biological compartments. Recognition of danger through the signal triad of pathogen-associated molecular patterns, damage-associated molecular patterns, and homeostasis-altering molecular processes induces profound intracellular metabolic reprogramming toward a predominantly aerobic glycolysis pattern. This shift supports early effector functions but leads to bioenergetic insufficiency, cytopathic hypoxia, and mitochondrial dysfunction.