Abstract
Background: Traumatic brain injury (TBI) is a global health challenge, leading to chronic cognitive and motor deficits. The limited neuroregenerative capacity of adult mammals hampers the development of effective therapies. In contrast, zebrafish exhibit remarkable brain regeneration, making them an ideal model for studying molecular and cellular mechanisms underlying TBI. Methods: This study established a telencephalic stab wound injury model in zebrafish to mimic TBI. Transcriptomic analyses were performed at control, 1-day post-lesion (dpl), 4 dpl, and 7 dpl to identify dynamic transcriptional changes during brain regeneration. Key signaling pathways were identified, and functional inhibition experiments were conducted to evaluate the role of specific pathways in the regenerative process. Results: Transcriptomic analysis revealed temporal transcriptional changes underlying brain regeneration, from early injury responses to proliferation and tissue remodeling. Key signaling pathways, including Insulin, FoxO, MAPK, mTOR, and NOD-like receptor signaling, were implicated in neural progenitor activation, proliferation, migration, and maintenance. The MAPK pathway, particularly p38α MAPK (MAPK14a), was identified as a critical regulator of the regenerative response. Functional inhibition of MAPK14a disrupted progenitor activation, impaired proliferation, and diminished neuronal and oligodendrocyte recovery, and led to increased cell death in neurogenic zones. Additionally, MAPK14a was found to influence Wnt/β-catenin and PI3K/AKT pathways further highlighted its integrative role in coordinating regeneration. Conclusions: This study provides insights into the molecular mechanisms of zebrafish brain regeneration, highlighting MAPK14a as a central regulator of neural repair. These findings may inform strategies for enhancing brain repair in mammals. Graphical : Supplementary Information: The online version contains supplementary material available at 10.1186/s12967-025-07400-7.