Folic Acid Promotes Peripheral Nerve Injury Repair via Regulating DNM3-AKT Pathway Through Mediating Methionine Cycle Metabolism.

Abstract

Emerging evidence suggests that folic acid (FA) supports nerve repair, but its beneficial effects in peripheral nerve injury (PNI) remains unclear. This study aims to investigate protective effects of FA against PNI and the underlying molecular mechanisms. High-performance liquid chromatography-tandem mass spectrometry was utilized for precise quantification of metabolites. A sciatic nerve crush injury model was established in rats, followed by assessments of cell proliferation, apoptosis, and motor function using CCK-8 assays, flow cytometry, and the balance beam test, respectively. Neuromorphological observations, electromyography, and ELISA were conducted to evaluate structural, electrophysiological, and biochemical parameters. In vitro, FA restored methionine cycle balance in Schwann cells and neurons disrupted by enzyme inhibition, improving cell viability, reducing apoptosis, and preserving cellular structure. In vivo, FA supplementation restored S-adenosylmethionine and homocysteine levels in a methionine metabolism disorder model and enhanced motor function, neural morphology, neuron survival, and electrophysiological recovery after PNI. Epigenetic analyses revealed that FA modulated DNA methylation and histone modifications of the DNM3 promoter, influencing gene expression. Furthermore, FA facilitated nerve repair via the DNM3-AKT pathway, regulating apoptosis, autophagy, and oxidative stress-related enzymes. These findings highlight FA's potential in promoting nerve repair through metabolic and epigenetic mechanisms.