CRM ‐1 Aggravates Stroke Injury by Promoting BANF1 ‐Mediated Unfolded Protein Response Through Inducing Nuclear Export of ALKBH5

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. m 6 A 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 m 6 A 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 m 6 A‐IGF2BP2/YTHDF1‐dependent manner. This cascade subsequently activated the PERK/eIF2α/CHOP ERS pathway.