AbstractBackgroundThe inability of damaged neurons to regenerate and of axons to establish new functional connections leads to permanent functional deficits after spinal cord injury (SCI). Although astrocyte reprogramming holds promise for neurorepair in various disease models, it is not sufficient on its own to achieve significant functional recovery.MethodsA rat SCI model was established using a spinal cord impactor. Seven days postsurgery, adeno‐associated virus were injected to overexpress the transcription factors NeuroD1 and Neurogenin‐2 (Ngn2) in the spinal cord. The rats were then trained to walk on a weight‐supported treadmill for 4 weeks, starting 14 days after modeling. The effects of these interventions on motor and sensory functions, as well as spinal cord tissue repair, were subsequently evaluated.ResultsThe combination of NeuroD1 and Ngn2 overexpression with weight‐supported exercise training significantly improved gait compared to either intervention alone. The group receiving the combined intervention exhibited enhanced sensitivity in sensory assessments. Immunofluorescence analysis revealed increased colocalization of astrocytes and microtubule‐associated protein 2–positive neurons in the injury area. These effects were more pronounced than those observed with spinal cord tissue repair alone. Additionally, the combined intervention significantly reduced glial scarring and the size of the injury area.ConclusionExercise intervention enhances the reprogramming effects of astrocytes and restores motor function, yielding better results than either intervention alone.