Effects of FGF4/HIF-1α axis-mediated neuronal glycolysis on neuropathic pain

The results showed that the pain threshold of rats decreased and that the structure of sciatic nerve tissue was damaged after CCI. Transcriptome sequencing of the sciatic nerve showed a significant increase in the expression levels of glycolysis-related indicators. Subsequent experiments confirmed that FGF4 expression was downregulated in the sciatic nerve and spinal dorsal horn after CCI, whereas the expression of hypoxia-inducible factor-1α (HIF-1α) and its key downstream glycolytic enzymes was upregulated, accompanied by increased levels of lactic acid and proinflammatory cytokines and decreased ATP levels.

The spinal dorsal horn exhibited both synaptic structural abnormalities and neuronal hyperexcitability. Inhibiting HIF-1α alleviated pain and suppressed glycolysis, whereas the overexpression of FGF4 specifically reversed the increase in HIF-1α expression, inhibited neuronal glycolysis, and reduced neuroinflammation and central sensitization, ultimately effectively relieving pain. This study reveals the core role of the FGF4/HIF-1α-mediated regulation of neuronal glycolysis in neuropathic pain, providing a new theoretical basis and experimental evidence for a deeper understanding of the metabolic mechanism of neuropathic pain and the development of targeted treatment strategies.