Metabolic-epigenetic coupling links glycolysis to macrophage-mediated myelin clearance after peripheral nerve injury

Macrophages are essential for myelin clearance following peripheral nerve injury, yet the mechanisms linking their functional heterogeneity to metabolic regulation remain unclear. Single-cell RNA sequencing was combined with functional assays to characterize macrophage heterogeneity and investigate the relationship between metabolic reprogramming and myelin clearance after peripheral nerve injury. A distinct macrophage subset enriched was identified after injury that exhibited elevated expression of glycolysis-related and phagocytosis-associated genes. Functional analyses demonstrated that glycolytic activity was positively associated with macrophage-mediated myelin clearance. Among candidate regulators, solute carrier family 2 member 6 was highly expressed in this subset, and its knockdown impaired glycolysis, lactate production, histone lactylation and myelin clearance capacity, effects that were partially rescued by metabolic intervention or lactate supplementation. In vivo, lactate administration was associated with enhanced myelin clearance and improved nerve structural and functional recovery. These findings provide new insights into the interplay between metabolic reprogramming and immune function in nerve injury. These results provide a mechanistic foundation for the development of metabolism-targeted therapeutic strategies to enhance peripheral nerve regeneration.