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Following peripheral nerve injury, myelin disintegration leads to substantial cholesterol release and accumulation, which has been suggested to aggravate neuroinflammation and hinder nerve repair in the central nervous system. However, whether cholesterol synthesis by SCs is detrimental or beneficial for peripheral nerve regeneration remains a critical and unresolved question. Present findings reveal that FDFT1, a key cholesterol biosynthesis enzyme, is downregulated within two weeks post\u2010injury but significantly upregulated thereafter. Conditional knockout (cKO) of\n                    <jats:italic>Fdft1<\/jats:italic>\n                    in SCs markedly impaired structural and functional recovery in mice after the sciatic nerve crush injury. Mechanistically, SCs\u2019\n                    <jats:italic>Fdft1<\/jats:italic>\n                    deficiency not only disrupts the cholesterol supply for remyelination but also suppresses the secretion of insulin\u2010like growth factor 1 (IGF1). This impairment of IGF1 signaling further attenuates the axonal regeneration by paracrine mechanisms and disrupts the remyelination via a novel IGF1R\/Rap1\/PI3K\/AKT axis within SCs. In conclusion, this work demonstrates that SC synthesized cholesterol plays dual roles in orchestrating nerve regeneration: it serves as an essential structural component of myelin and also works as a regulator of IGF1 expression to enhance axonal regeneration and remyelination.\n                  <\/jats:p>","DOI":"10.1002\/advs.202520323","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T06:35:51Z","timestamp":1767594951000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Schwann Cell Synthesized Cholesterol Orchestrates Peripheral Nerve Regeneration via Structural and IGF1\u2010Dependent Signaling Mechanisms"],"prefix":"10.1002","volume":"13","author":[{"given":"Shuyi","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Histology and Embryology, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, National Demonstration 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