Abstract: Traumatic spinal cord injury (SCI) is a devastating central nervous system (CNS) disorder characterized by significant neurological dysfunction and sensory loss, and effective therapies that prevent neuronal loss and functional recovery remain elusive. After SCI, lesions are surrounded by neuroprotective borders formed by newly proliferated reactive astrocytes. Astrocyte proliferation and activation mediate the formation and function of the glial scar and influence the balance between protection and inflammation. However, molecular mechanisms that regulate these essential astrocytic responses are still poorly understood. Our recent study highlights the DNA/RNA-binding protein, heterogeneous nuclear ribonucleoprotein U (Hnrnpu), as a potential endogenous regulator in astrocyte proliferation, migration, and subsequent scar formation (Quan et al., 2025). Notably, Hnrnpu appears to selectively enhance the expression of permissive extracellular matrix (ECM) molecules, thereby promoting axon regrowth and revealing a pro-regenerative astrocyte response. These findings deepen the understanding of the intrinsic mechanisms that control astrocyte response and provide a new regulatory mechanism involved in reactive astrocyte proliferation and resulting beneficial effects on CNS injury repair. Overall, this work demonstrates the essential function of glial pathology in response to CNS injury and points to a promising therapeutic approach for promoting axon regeneration through targeting astrocytic Hnrnpu to modulate glial scar formation