Sez6l promotes neuropathic pain via Wnt5a/Ca2+ pathways in dorsal root ganglion

Background Neuropathic pain (NP) is a prevalent chronic pain disorder that severely impairs the physical and mental health of patients, affecting 6.9%–10% of the general population. The dorsal root ganglion (DRG) is a crucial locus in the pathogenesis of NP. However, the underlying mechanisms by which DRGs contribute to this condition remain incompletely understood. Methods High-throughput sequencing data of DRGs was downloaded from the Gene Expression Omnibus (GEO) and integrated for analysis. Differential expression analysis combined with multiple machine learning methods was employed to identify candidate genes associated with NP in DRGs. The spared nerve injury (SNI) model was used to assess gene expression patterns. Small interfering RNA-mediated knockdown of the target gene was performed to evaluate its functional role. Bioinformatics analysis and chromatin immunoprecipitation (ChIP) experiments were conducted to explore the transcriptional regulation of the target gene. Results Sez6l was identified as a candidate gene upregulated in DRGs. In the SNI model, Sez6l was significantly upregulated. Knockdown of Sez6l reduced the expression levels of inflammatory cytokines (IL-6, TNF-α, and IL-1β) and alleviated mechanical allodynia and thermal hyperalgesia in SNI mice. Bioinformatics analysis and ChIP experiments suggested that Foxo1 may enhance the transcription and expression of Sez6l. Mechanistically, Sez6l promoted NP by activating the Wnt5a/Ca 2+ signaling pathway in DRGs. Conclusion Our findings suggest that Sez6l, which is transcriptionally regulated by Foxo1, facilitates neuropathic pain through activating the Wnt5a/Ca 2+ signaling pathway in DRGs.