Yi Yang, Zeming Xiang, Xingwei Zhao, Mowei Kong, Yuling Jing, Chunxiang Zhang
Peripheral nerve injury poses a significant medical challenge, as nerve regeneration typically occurs slowly and incompletely. Schwann cells, the primary glial cells in the peripheral nervous system, exhibit considerable plasticity that enables them to initiate specialized repair mechanisms to stimulate axonal regeneration and remyelination. A central aspect of this process is the role of the transcription factor c-Jun in the dedifferentiation of Schwann cells. c-Jun-driven Schwann cells promote myelin clearance, provide trophic support, and facilitate the formation of regenerative pathways. In this review, we explore c-Jun-driven Schwann cell repair at the systems level by integrating insights from signaling pathways, single-cell and spatial transcriptomics, proteomics, metabolomics, and high-resolution in vivo imaging. We emphasize the spatiotemporal dynamics of repair Schwann cells, their functional heterogeneity, and their interactions with neighboring cell types. Findings from this review have revealed the presence of cells containing both axons and immune cells. Furthermore, emerging technologies such as CRISPR-based epigenetic editing, optogenetics, nanomedicine, and biomaterial-guided tissue engineering offer novel approaches to regulate c-Jun signaling and enhance nerve repair outcomes. Preclinical and translational studies indicate that these methods can lead to more successful repairs; however, transitioning from laboratory research to clinical application requires further investigation to ensure long-term efficacy and the development of standardized treatment protocols. Understanding the c-Jun regulatory network and harnessing the distinct functional properties of Schwann cells hold great promise for overcoming the remaining challenges in peripheral nerve regeneration, paving the way for precise therapies for neuropathies and nerve injuries in the future.