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The glial scar that forms at the site of injury after spinal cord injury (SCI) is an important physical and biochemical barrier that prevents axonal regeneration and thus delays functional recovery. Ski is a multifunctional transcriptional co-regulator that is involved in a wide range of physiological and pathological processes in humans. Previous studies by our group found that Ski is significantly upregulated in the spinal cord after in vivo injury and in astrocytes after in vitro activation, suggesting that Ski may be a novel molecule regulating astrocyte activation after spinal cord injury. Further studies revealed that knockdown or overexpression intervention of Ski expression could significantly affect the proliferation and migration of activated astrocytes. To further verify the effect of knockdown of Ski expression in vivo on glial scar formation and neurological function after spinal cord injury, we prepared a rat spinal cord injury model using Allen's percussion method and used lentivirus as a vector to mediate the downregulation of Ski in the injured spinal cord. The results showed that knockdown of Ski expression after spinal cord injury significantly suppressed the expression of glial fibrillary acidic protein (Gfap) and vimentin, hallmark molecules of glial scarring, and increased the expression of neurofilament protein-200 (Nf-200) and growth-associated protein (Gap43), key molecules of axon regeneration, as well as Synaptophysin, a key molecule of synapse formation expression. In addition, knockdown of Ski after spinal cord injury also promoted the recovery of motor function. Taken together, these results suggest that Ski is able to inhibit the expression of key molecules of glial scar formation, and at the same time promotes the expression of molecules that are markers of axonal regeneration and synapse formation after spinal cord injury, making it a potential target for targeted therapy after spinal cord injury., Competing Interests: Declarations Conflict of interest The authors declare no competing interests. Ethical Approval All experimental steps were performed in accordance with the Chinese guidelines for animal protection and welfare and were approved by the Medical Ethics Committee of the Lanzhou University Second Hospital., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)