Abstract Body: RNA-binding proteins (RBPs) regulate post-transcriptional gene regulation by dynamically interacting with mRNAs to regulate their metabolism by both transcription-dependent and independent mechanisms. Many noncoding RNAs (ncRNAs) are known to act concertedly to regulate the function of other ncRNAs and the stability of RBPs, indicating the functional complexity of the ncRNA/RBP interactions in regulating mRNA functionality. Differential expression of RBPs and ncRNAs was shown to modulate post-stroke pathophysiology. However, the functional significance of the intricate network of the ncRNAs/RBPs in ischemic stroke is not yet explored. Here, we showed that focal ischemia in adult male mice induces the expression of lncRNA NORAD (long ncRNA activated upon DNA damage) and circular RNA circPum-1 (encoded by Pumilio-1; Pum-1, which is a NORAD interacting RBP). This is accompanied by a significant decrease in the Pum-1 protein levels. Bioinformatics showed a strong interaction between NORAD and circPum-1 with a hybridization energy of -30.2 kcal/mol. Furthermore, RNA pulldown experiments showed a significant increase in the enrichment of NORAD with Pum-1 in the post-stroke brain. These results suggest that NORAD interaction with Pum-1 might be responsible for Pum-1 protein degradation, supporting the notion that NORAD is a molecular decoy of Pum-1. Additionally, post-stroke Pum-1 insufficiency promoted the expression of its target mRNAs MyD88, HMGB-1, and BNIP2, which mediate inflammation and apoptosis. Moreover, Pum-1 haploinsufficiency exacerbated ischemic brain damage. Although circPum-1 knockdown did not significantly impact the post-stroke infarct volume and motor function, NORAD knockdown and its deletion significantly reduced the infarct volume and improved the motor function. This underscores the complexity of ncRNAs and RBP interaction in regulating post-stroke pathophysiology