Nucleotide Metabolic Reprogramming in Sepsis: From Immune-Cell Fate to Organ Injury and Precision Therapeutics

Sepsis is a life-threatening syndrome characterized by concurrent inflammation, immunosuppression, endothelial dysfunction and metabolic failure. Although current immunometabolic research primarily focuses on glycolysis, mitochondrial respiration and lipid metabolism, nucleotide metabolism links biosynthesis, redox homeostasis, epigenetic regulation and extracellular danger signalling. This Review synthesizes evidence for altered purine and pyrimidine synthesis, ribonucleotide reduction, nucleoside salvage and purinergic signalling across immune-cell populations in sepsis. We distinguish clinical observations from mechanistic evidence in experimental sepsis and hypotheses extrapolated from cancer or immune-mediated disease. Human observational studies support involvement of the extracellular ATP-CD39/CD73-adenosine axis in sepsis, while experimental studies provide complementary mechanistic evidence. By contrast, the roles of DHODH, RRM2 and the uridine-UPP1 salvage pathway remain predominantly preclinical, particularly in ferroptosis and acute organ injury. We propose that nucleotide metabolism functions as a time-, cell- and compartment-dependent regulatory network rather than a uniformly activated pathway. Clinical translation will require longitudinal metabolite-enzyme-receptor profiling, isotope-resolved flux analysis, spatial and single-cell approaches, and biomarker-defined therapeutic windows. Such strategies may enable nucleotide-directed interventions to complement antimicrobial treatment and organ support without compromising protective immunity.