Abstract
ABSTRACT
Peripheral nerve injury (PNI) affects 13–23 individuals per 100,000 annually, and functional recovery hinges on faithful remyelination of regenerating axons by Schwann cells (SCs). This review integrates the complete molecular logic governing the transition from injury‐induced SC plasticity to mature myelin regeneration. The hierarchical transcriptional program—from SOX10 pioneer factor engagement through OCT6‐mediated promyelinating transition to KROX20/EGR2‐driven activation of compact myelin genes—and the instructive role of axonal Neuregulin‐1 Type III signaling are dissected. Wallerian degeneration via the NMNAT2–SARM1‐mediated axon degeneration cascade, c‐JUN‐dependent SC reprogramming, and the epigenetic and noncoding RNA mechanisms that re‐engage myelination are examined. The immune microenvironment is considered as a temporally layered network in which macrophage polarization, macrophage‐to‐myofibroblast transition, and regulatory T cell activity coordinate the transition from inflammation to repair. Finally, this review critically evaluates emerging therapeutic strategies—including Neuregulin‐1 supplementation, SC transplantation, nerve guidance conduits, electrical stimulation, and senolytic clearance of aged SCs—and argues that rationally sequenced combination therapies will be required to achieve transformative improvements in functional recovery after severe PNI. This review provides a mechanistic roadmap for designing next‐generation regenerative strategies aimed at restoring saltatory conduction.