RNA-binding protein with serine-rich domain 1 (RNPS1) is essential for modulating mRNA metabolism, but its role in ischemic stroke is unknown. In this study, we found that RNPS1 expression was significantly up-regulated in the brains of ischemic stroke mice and primary cortical neurons after oxygen-glucose deprivation (OGD) treatment. Knockdown of RNPS1 significantly aggravated ischemic brain injury after middle cerebral artery occlusion (MCAO) and promoted neuronal death. In addition, knockdown of RNPS1 exacerbated ischemia induced neuronal apoptosis, and downregulated the expression of anti-apoptotic proteins Bcl-xL and Mcl-1. Our study suggested that RNPS1 might be a potential therapeutic target for alleviating neuronal death in ischemic stroke. (C) 2019 Elsevier Inc. All rights reserved.