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Spinal cord injury (SCI) causes increased apoptosis of neurons, leading to irreversible dysfunction of the spinal cord. In this study, we investigated the effects of the progression of SCI and potential regulation of apoptosis after the Pleckstrin homology (PH) domain and leucine rich repeat protein phosphatase 1 (PHLPP1) gene was silenced.Spinal cord injection, and neuronal transfection with a recombinant adenovirus vector encoding small interfering RNA (siRNA) against PHLPP1 (AdsiPHLPP1) successfully silenced PHLPP1. These created in vivo and in vitro PHLPP1-silenced models, respectively, resulting in stable expression of the transgene in neurons.The results showed that silencing of PHLPP1 evidently reduced levels of the nuclear factor erythroid 2-related factor 2 (Nrf2) after SCI. Western blot analysis revealed that the mice injected with AdsiPHLPP1 showed increased the expression of pro-apoptotic factors (Bax and cleaved-caspase 3), and reduced levels of neurotrophic (BDNF) and anti-apoptotic (Bcl-2) factors, both in vivo and in vitro. The motor function of AdsiPHLPP1-injected mice was restored more slowly than that of wild type (WT) mice. In addition, the number of motor neurons surviving in the anterior horn of the spinal cord was also reduced after SCI.Our results confirm that silencing of PHLPP1 promotes neuronal apoptosis and inhibits functional recovery after injury in vivo and in vitro. Consequently, PHLPP1 represents a potential therapeutic target gene for the clinical treatment of SCI.