FASEB J. 2026 Jul 31;40(14):e72112. doi: 10.1096/fj.202601304R.
ABSTRACT
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.
PMID:42440016 | DOI:10.1096/fj.202601304R