CRM-1 Aggravates Stroke Injury by Promoting BANF1-Mediated Unfolded Protein Response Through Inducing Nuclear Export...

The activation of endoplasmic reticulum stress (ERS), specifically the PERK/eIF2α/CHOP signaling, is a recognized consequence of ischemic stroke. However, the roles and mechanisms of CRM-1 regulating ERS in stroke are poorly elucidated. A murine model of stroke was generated via transient middle cerebral artery occlusion (MCAO). The endpoints included TTC-derived infarct volume, H&E/TUNEL histopathology, p-PERK immunohistochemistry, and Western blot. Oxygen-glucose deprivation/reoxygenation (OGD/R) was employed in HT22 neurons. The CRM1-ALKBH5 interaction and subcellular distribution were assessed by co-immunoprecipitation (co-IP), cytoplasm-nucleus fractionation, and confocal microscopy. m⁶A regulation of BANF1 was examined using MeRIP-qPCR, RIP-qPCR, and a dual-luciferase reporter assay. Knockdown of CRM-1 reduced the infarct size, decreased ER stress activation, decreased apoptosis in vivo, and improved cell viability after OGD/R. CRM-1 was attached to ALKBH5 and promoted its export from the nucleus, which increased m⁶A modification and expression on BANF1. IGF2BP2 and YTHDF1, respectively, enhanced the stability and translation of BANF1 mRNA, thereby upregulating its expression. BANF1 overexpression restored PERK/eIF2α/CHOP activation and apoptosis in the CRM-1 knockdown context. CRM-1 exacerbated ischemic stroke injury by exporting ALKBH5 to upregulate BANF1 in an m⁶A-IGF2BP2/YTHDF1-dependent manner. This cascade subsequently activated the PERK/eIF2α/CHOP ERS pathway.