Exogenous resolvin D2 alleviates diabetic neuropathic pain by regulating microglial fatty acid metabolism and phenotypic polarization
- 1Department of Pain Management, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
- 2Department of Pain Management, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; Shandong University, Jinan, Shandong, 250100, China
- 3Department of Pain Management, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; Corresponding author.
Abstract
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.
Related
- Re-Du-Ning Alleviates Airway-Intestinal Inflammation of COPD Rats by Regulating Glycerophospholipid Metabolism and Modulating Gut Microbiome
- Crocin alleviates renal fibrosis through inhibiting mitochondrial dysfunction via regulating HOXD8/PGC‑1α pathways
- Ligustrazine Combined with Sinomenine Alleviates Central Sensitization in CCI-Induced Neuropathic Pain in Rats by Restoring Metabolic Homeostasis in the Spinal Dorsal Horn.
- Dysfunction of lipid metabolism and lysosomal capacity: at the core of microglial aging?
- Knockdown of CLEC7A Alleviates Ischemic Brain Injury by an Anti-Inflammatory Microglial Phenotype via the CXCL1/CXCR2 Axis.
BibTeX
@article{ma2026exogenous,
title = {{Exogenous resolvin D2 alleviates diabetic neuropathic pain by regulating microglial fatty acid metabolism and phenotypic polarization}},
author = {Xinyi Ma and Xueying Wang and Lutong Yue and Keyang Duan and Yuchen Hao and Xian'ge Liu and Tao Sun},
journal = {Neurotherapeutics},
year = {2026},
month = oct,
doi = {10.1016/j.neurot.2026.e01111},
url = {https://doi.org/10.1016/j.neurot.2026.e01111},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Exogenous resolvin D2 alleviates diabetic neuropathic pain by regulating microglial fatty acid metabolism and phenotypic polarization
AU - Xinyi Ma
AU - Xueying Wang
AU - Lutong Yue
AU - Keyang Duan
AU - Yuchen Hao
AU - Xian'ge Liu
AU - Tao Sun
PY - 2026
DA - 2026/10/27
JO - Neurotherapeutics
DO - 10.1016/j.neurot.2026.e01111
UR - https://doi.org/10.1016/j.neurot.2026.e01111
AB - 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.
SN - 1878-7479
SN - 1933-7213
ER -