CIRBP exerts neuroprotective effects in ischemic injury by inhibiting IFN-I signaling

Ischemic brain injury (IBI) is a severe neurological disorder with poorly defined pathogenesis and limited treatments. Cold-inducible RNA-binding protein (CIRBP) mediates stress responses, yet its post-transcriptional regulatory role in IBI remains unclear. This study investigated CIRBP's function and mechanisms to provide IBI therapeutic insights.

An oxygen-glucose deprivation/reoxygenation (OGD/R) model was established in differentiated PC12 cells to mimic IBI in vitro. CIRBP-overexpressing PC12 cells were constructed, and cell viability, apoptosis and oxidative stress were detected. RNA-seq identified CIRBP-regulated differentially expressed genes (DEGs) and alternative splicing (AS) events; PPI networks screened hub genes, and RIP-seq characterized CIRBP's RNA-binding profile.

CIRBP overexpression significantly attenuated OGD/R-induced neuronal damage by improving cell morphology, enhancing viability, reducing apoptosis and suppressing oxidative stress. RNA-seq revealed 114 CIRBP-regulated DEGs, with downregulated genes enriched in type I interferon (IFN-I) signaling and neuroinflammation; Oas2 was the core hub gene, with multiple IFN-I-related hub genes identified. CIRBP regulated 506 AS events (mainly IntronR, A5SS, A3SS) linked to axon extension and NF-κB regulation. RIP-seq showed CIRBP preferentially bound to CDS, Nc-exon and antisense regions, recognized miRNA-targeted motifs, and Prrc2b was a potential regulator of CIRBP-binding mRNAs.

CIRBP exerts neuroprotection in OGD/R models by inhibiting oxidative stress and IFN-I-related neuroinflammation, and regulating AS of IBI-associated genes. It has a distinct RNA-binding pattern and may crosstalk with miRNAs in post-transcriptional regulation, highlighting CIRBP as a potential therapeutic target and its regulated genes/AS events as promising IBI biomarkers.