Exogenous resolvin D2 alleviates diabetic neuropathic pain by regulating microglial fatty acid metabolism and phenotypic polarization.

Diabetic neuropathic pain (DNP) is a common and intractable complication of diabetes with limited therapeutic options. Distinct from traditional NF-κB or MAPK inflammatory pathways, resolvin D2 (RvD2) alleviates DNP through metabolic reprogramming-a novel mechanism that remains largely unexplored. Untargeted metabolomics analysis of the spinal cord from DNP model mice and RvD2-treated mice revealed significant alterations in fatty acid oxidation (FAO)-related metabolites between the two groups. Functionally, RvD2 effectively alleviated hyperalgesia in DNP mice and ameliorated the FAO dysfunction associated with a pro-inflammatory microglial state. Mechanistically, RvD2 upregulated the expression of peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase 1a (CPT1a), thereby activating the PPARα/CPT1a axis to enhance FAO. This metabolic shift consequently augmented ATP production, suppressed reactive oxygen species (ROS) levels, and diminished succinate accumulation, which in turn blocked hypoxia-inducible factor-1α (HIF-1α)-mediated pro-inflammatory signaling. Concurrently, RvD2 elevated the acetyl-CoA pool, promoting histone acetylation and chromatin accessibility at the promoters of pro-resolving polarization-related genes, which drove microglia toward a pro-resolving phenotype. Notably, the specific CPT1a inhibitor etomoxir partially reversed these protective effects of RvD2. In conclusion, RvD2 alleviates DNP by driving microglial pro-resolving polarization through a CPT1a-mediated metabolic-epigenetic axis, providing a promising therapeutic target and a potent candidate agent for the clinical management of DNP.