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Peripheral nerves possess a degree of regenerative ability, and actively promoting their recovery can help restore the sensory and functional capacities of tissues. The neuropeptide calcitonin gene\u2010related peptide (CGRP) is believed to regulate the repair of injured peripheral nerves, with neuronal transient receptor potential vanilloid type 1 (TRPV1) potentially serving as a crucial upstream factor. In this study, we established a mouse model of sciatic nerve (SN) crush injury and found that intrathecal injection of capsaicin (Cap) activated the neuronal TRPV1\u2010CGRP axis, thereby promoting SN repair. Conversely, the application of capsazepine (Cpz), which inhibits the neuronal TRPV1\u2010CGRP axis, delayed SN repair. Local restoration of CGRP expression at the injury site enhanced the repair process. In\u00a0vitro experiments, we employed the rat Schwann cell (SC) line RSC96 to establish an indirect co\u2010culture model of neurons and SCs. We observed that the proliferation, migration, expression of myelination\u2010associated proteins, and neurotrophic secretion functions of RSC96 cells are positively correlated with the degree of activation of neuronal TRPV1. Inhibition of neuronal TRPV1, followed by the restoration of CGRP levels, improved these functions in RSC96 cells. Furthermore, activation of the neuronal TRPV1\u2010CGRP axis resulted in an upregulation of extracellular signal\u2010regulated kinases 1\/2 (ERK1\/2) phosphorylation levels and an increase in hypoxia\u2010inducible factor 1\u03b1 (HIF\u20101\u03b1) accumulation in RSC96 cells, thereby promoting their proliferation and migration. In summary, this study demonstrates that neuronal TRPV1\u2010CGRP axis can regulate biological behavior of SCs and axon regeneration by activating the ERK\/HIF\u20101 signaling pathway following peripheral nerve injury. This finding clarifies the role of CGRP in neuroregulatory networks and provides a novel reference point for the development of drugs and biomaterials for treating nerve damage.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc16281-fig-0011-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.16281","type":"journal-article","created":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T20:10:55Z","timestamp":1736539855000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Neuronal <scp>TRPV1<\/scp>\u2010<scp>CGRP<\/scp> axis regulates peripheral nerve regeneration through <scp>ERK<\/scp>\/<scp>HIF<\/scp>\u20101 signaling pathway"],"prefix":"10.1111","volume":"169","author":[{"given":"Huiling","family":"Che","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral Diseases &amp; 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