Melatonin in Peripheral Nerve Regeneration: Molecular Mechanisms, Schwann Cell Dynamics, and Translational Therapeutic Potential.

Peripheral nerve injury (PNI) presents a significant clinical challenge often resulting in long-term functional disability. Following injury, successful regeneration heavily depends on the cellular plasticity of Schwann cells (SCs) to undergo dedifferentiation, proliferate, and guide axonal growth. Recently, the pineal hormone melatonin has emerged as a promising therapeutic candidate due to its potent antioxidant properties and ability to modulate SC biological behavior. However, its exact molecular mechanisms and direct impact on SC proliferation remain fragmented across literature. Following PRISMA 2020 guidelines and registered on PROSPERO (CRD420261373030), a systematic search was conducted across Medline via PubMed, Scopus, and Web of Science up to April 1, 2026. Original in vitro and in vivo studies evaluating melatonin's effects on SC proliferation and PNI models were included. Data extraction focused on signaling pathways, histological outcomes, and functional recovery. Risk of bias was assessed using QUIN for in vitro and SYRCLE for in vivo studies. Twenty-six studies (12 in vivo, 3 in vitro, 11 mixed) were analyzed. In vitro, melatonin administration was frequently associated with dose-dependent mitogenic responses in RSC96 and primary SCs, operating primarily via MT1 receptor interaction and downstream activation of the Ras/Raf/ERK-MAPK and Shh signaling pathways. It supported SC dedifferentiation alongside Sox2 upregulation and alternative FAK activation, while preserving cell viability under oxidative stress via Parkin-mediated mitophagy. In vivo, melatonin treatment was correlated with increased myelin sheath thickness, higher axon density, and elevated SC infiltration across sciatic, cranial, and brachial plexus models. These structural changes were accompanied by functional recovery trends, higher CMAP amplitudes, and reduced lipid peroxidation markers (lowered MDA/MPO). Advanced delivery platforms, including 3D-printed scaffolds and electrospun magnetic nanoparticles, achieved sustained local melatonin release in experimental models. Preclinical evidence indicates that melatonin modulates Schwann cell proliferation, migration, and cytoprotection through receptor-dependent and antioxidant mechanisms. These findings offer a foundational, evidence-based rationale for further investigation in large-animal models and prospective clinical trial designs.