Macrophage metabolic reprogramming in sepsis-associated acute lung injury: mechanisms and therapeutic strategies

Sepsis-associated acute lung injury (S-ALI) remains a life-threatening condition with high mortality and limited therapeutic options. Macrophages, as key sentinels of innate immunity, exhibit remarkable heterogeneity and functional plasticity. These properties are fundamentally driven by metabolic reprogramming, which tailors their effector functions to specific microenvironmental demands. Beyond the traditional M1/M2 binary classification, macrophage activation is now appreciated as a continuous functional spectrum. Pro-inflammatory macrophages preferentially utilize aerobic glycolysis and the pentose phosphate pathway, coupled with suppressed oxidative phosphorylation (OXPHOS), whereas reparative macrophages rely predominantly on OXPHOS and fatty acid oxidation (FAO). Key glycolytic enzymes such as PFKFB3 and PKM2, the transcriptional regulator HIF-1α, and TCA cycle intermediates including succinate and itaconate serve as critical metabolic checkpoints governing macrophage inflammatory responses. During S-ALI, the metabolic landscape undergoes dynamic temporal shifts: the early hyperinflammatory phase is characterized by enhanced glycolysis, while the late immunosuppressive phase exhibits impaired OXPHOS and FAO. This review synthesizes recent advances in understanding how metabolic reprogramming orchestrates macrophage polarization during S-ALI, encompassing glycolysis, the TCA cycle, FAO, and amino acid metabolism. Natural compounds, pharmacological inhibitors, and innovative delivery platforms have shown promise in reprogramming macrophage metabolism to restore immune homeostasis. Notable examples include aerosolized CRISPR/Cas9 nanotherapeutics, biomimetic nanoplatforms, pH-responsive nanoparticles, and engineered exosomes. However, challenges such as broad cytotoxicity, limited macrophage selectivity, incomplete pharmacokinetic characterization, and the timing of intervention in the evolving septic milieu must be addressed. Future strategies should focus on developing cell-type-restricted delivery systems, validating targets in human-relevant models, and designing phase-specific interventions tailored to the metabolic trajectory of S-ALI.