NRN1 inhibits neuronal apoptosis and improves motor recovery after spinal cord injury via binding to FZD2 to activate the GSK-3β/Nrf2 pathway.

Neuritin 1 (NRN1) is a neurotrophic factor known to protect neurons from damage and cell death; however, its role and mechanism in cervical spinal cord injury (CSCI) remain unclear. In this study, we investigated the function of NRN1 using oxygen-glucose deprivation (OGD)-treated PC12 cells and a rat model of CSCI established by anterior cervical screw compression. In vitro, NRN1 overexpression promoted neurite outgrowth, attenuated oxidative stress, and inhibited apoptosis in OGD‑exposed PC12 cells, while NRN1 knockdown showed opposite results. Mechanistically, co-immunoprecipitation and immunofluorescence confirmed that NRN1 interacts with FZD2. In OGD-treated PC12 cells, overexpression of FZD2 reversed the neuronal damage induced by NRN1 silencing, reducing oxidative stress and the number of apoptotic cells. Furthermore, NRN1‑mediated neuroprotection was dependent on activation of the GSK‑3β/Nrf2 pathway, since pharmacological inhibition of Nrf2 with ML385 abrogated the protective effects of NRN1. In vivo, decreased expression of NRN1 was observed at the site of spinal cord injury in rats. Notably, intramedullary delivery of adeno‑associated virus (AAV) encoding NRN1 restored NRN1 levels, significantly improved motor function, reduced neuronal apoptosis, and alleviated oxidative stress in spinal cord tissue. Collectively, our findings demonstrate that NRN1 exerts neuroprotective effects against CSCI by binding to FZD2 and activating the GSK‑3β/Nrf2 signaling pathway, suggesting that targeting NRN1 may represent a novel therapeutic strategy for promoting motor recovery in CSCI patients.