Hydrogen Peroxide Modulates the Timely Activation of Jun and Erk in Schwann Cells at the Injury Site and Is Required for Motor Axon Regeneration.

Peripheral nervous system (PNS) neurons, including motor neurons (MNs), possess a remarkable ability to regenerate and reinnervate target muscles following nerve injury. This process is orchestrated by a combination of intrinsic neuronal properties and extrinsic factors, with Schwann cells (SCs) playing a central role. Upon injury, SCs transition into a repair phenotype that allows axonal regeneration through molecular signaling and structural guidance. However, the identity of the SCs' reprogramming factors is only partially known. We previously identified hydrogen peroxide (H(2)O(2)) as an early and key driver of nerve repair, inducing gene expression rewiring in SCs to support nerve re-growth. In this study, we quantitatively assessed the role of H(2)O(2) in the activation of key pro-regenerative signaling pathways in SCs following sciatic nerve compression, specifically the extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun, which are essential for functional nerve recovery. Notably, we found that H(2)O(2) neutralization does not impact degeneration, but it significantly affects the regenerative response. Collectively, our findings establish H(2)O(2) as a promising regulator of the Schwann cell injury response at the injury site, linking oxidative signaling to the molecular mechanisms governing nerve regeneration.