<p>Spinal cord injury (SCI) has a high mortality and disability rate. Endoplasmic reticulum (ER) stress induces neuronal apoptosis and participates in the regulation of SCI. LncRNA ZFAS1 can participate in the regulation of SCI by influencing ER stress; however, its mechanism is worth further exploring. The molecular mechanism of lncRNA ZFAS1 regulating spinal cord injury was evaluated by in vitro and in vivo experiments. We established an SCI model in vitro by inducing mouse microglia (BV-2) with LPS. The regulation of SCI was verified by transfection of shRNA knockdown lncRNA ZFAS1 and CNPY2. The expression levels of related genes and proteins were detected by qPCR and western blot. The proportion of apoptosis was analyzed by flow cytometry and TUNEL staining. RIP and RNA pull down verified that lncRNA ZFAS1 combined with SRSF1 stabilized CNPY2 mRNA. It was verified that lncRNA ZFAS1 promoted ER stress and accelerated SCI injury in SCI mice model. Our results showed that the expression of lncRNA ZFAS1 and CNPY2 increased in SCI cell model, which was related to SCI injury. Knocking down lncRNA ZFAS1 or CNPY2 could inhibit ER stress and reduce apoptosis of BV-2 cells. Inhibition of lncRNA ZFAS1 in SCI mice increased the number of spinal cord neurons and ER stress response, and improved SCI injury in mice. Molecular experiments confirmed that lncRNA ZFAS1 stabilized CNPY2 mRNA by binding to SRSF1. And the lncRNA ZFAS1/CNPY2 axis was involved in regulating ER stress and apoptosis of BV-2 cells. LncRNA ZFAS1 stabilized CNPY2 by combining with SRSF1, which led to ER stress in microglia and promoted SCI. LncRNA ZFAS1 may be a potential target gene for the prevention and treatment of SCI.</p>