Myelination and Remyelination in Peripheral Nerve Injury: Mechanisms, Regulation, and Therapeutic Perspectives

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.