Omega-3 Fatty Acids Mitigate Neuropathic Pain by Modulating Ferroptosis, Glutamate and Lipid Remodeling

Pain behaviors were assessed using the Hargreaves and CatWalk tests, and dorsal root ganglia tissue was harvested for RNA sequencing. Quantitative Real-Time PCR was used to confirm expression of promising RNA-seq transcripts. The clinical study enrolled 40 patients with type 2 diabetes and neuropathy who received -3 supplementation for three months.

Plasma samples were analyzed via metabolomics and lipidomics. In rats, -3 significantly reduced hyperalgesia and allodynia and improved locomotion by day 7 post-CCI (p < 0.05). RNA-seq data revealed downregulation of pain-associated genes including Scn10a (log₂FC = -1.3, p = 0.006), Trpa1(log₂FC = -1.4, p < 0.001), and P2rx7 (log₂FC = -0.73, p = 0.056), alongside modulation of the ferroptosis pathway gene Gpx4 (log₂FC = 1.1, p = 0.01).

Markers of satellite glial cells, such as Gfap (log₂FC = 1.64, p = 0.0015) and Glul(log₂FC = 0.90, p = 0.023), were upregulated, suggesting enhanced neuronal repair and glutamate regulation. Genes involved in lipid metabolism, including Fabp7 (log₂FC = 0.39) and Fasn (log₂FC = -0.45), also showed significant shifts. Activation of selenoamino acid metabolism in rats corresponded with metabolomics analysis results in human subjects, indicating enhanced antioxidant capacity and potential inhibition of ferroptosis.

Lipidomics in the human cohort demonstrated increased triglyceride catabolism (DG→MG, z = 2.03, PNPLA2) and a reduction in peroxidation-prone lipids (DG[40:6] →PC[40:6], z = 6.36, CHPT1). Together, these findings indicate that -3 reduce NP through modulation of ferroptosis, glutamate homeostasis, lipid peroxidation, and glial function