Schwann Cell Synthesized Cholesterol Orchestrates Peripheral Nerve Regeneration via Structural and IGF1‐Dependent Signaling Mechanisms

ABSTRACT Peripheral nerve myelin is the most cholesterol‐rich structure in the body, with the majority of cholesterol being synthesized by Schwann Cells (SCs). 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‐injury but significantly upregulated thereafter. Conditional knockout (cKO) of Fdft1 in SCs markedly impaired structural and functional recovery in mice after the sciatic nerve crush injury. Mechanistically, SCs’ Fdft1 deficiency not only disrupts the cholesterol supply for remyelination but also suppresses the secretion of insulin‐like 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.