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Lasting endoplasmic reticulum (ER) stress can drive neurological disorders. Targeting ER stress shows potential neuroprotective effects against stroke. However, the role of ER stress in CCH pathological processes and the effects of targeting ER stress on brain ischemia are unclear. Here, a CCH rat model was established by bilateral common carotid artery occlusion. Rats were treated with 4-PBA, URB597, or both for 4\u00a0weeks. Neuronal morphological damage was detected using hematoxylin\u2013eosin staining. The expression levels of the ER stress\u2013ASK1 cascade-related proteins GRP78, IRE1\u03b1, TRAF2, CHOP, Caspase-12, ASK1, p-ASK1, JNK, and p-JNK were assessed by Western blot. The mRNA levels of TNF-\u03b1, IL-1\u03b2, and iNOS were assessed by RT-PCR. For oxygen\u2013glucose deprivation experiments, mouse hippocampal HT22 neurons were used. Apoptosis of the hippocampus and HT22 cells was detected by TUNEL staining and Annexin V-FITC analysis, respectively. CCH evoked ER stress with increased expression of GRP78, IRE1\u03b1, TRAF2, CHOP, and Caspase-12. Co-immunoprecipitation experiments confirmed the interaction between TRAF2 and ASK1. ASK1\/JNK signaling, inflammatory cytokines, and neuronal apoptosis were enhanced, accompanied by persistent ER stress; these were reversed by 4-PBA and URB597. Furthermore, the ASK1 inhibitor GS4997 and 4-PBA displayed synergistic anti-apoptotic effects in cells with oxygen\u2013glucose deprivation. In summary, ER stress-induced apoptosis in CCH is associated with the IRE1\u03b1\/TRAF2\/ASK1\/JNK signaling pathway. Targeting the ER stress\u2013ASK1 cascade could be a novel therapeutic approach for ischemic cerebrovascular diseases.<\/jats:p>","DOI":"10.1007\/s10753-024-01989-5","type":"journal-article","created":{"date-parts":[[2024,2,24]],"date-time":"2024-02-24T16:02:27Z","timestamp":1708790547000},"page":"1479-1490","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Inhibition of Endoplasmic Reticulum Stress Improves Chronic Ischemic Hippocampal Damage Associated with Suppression of IRE1\u03b1\/TRAF2\/ASK1\/JNK-Dependent Apoptosis"],"prefix":"10.1007","volume":"47","author":[{"given":"Kai","family":"Kang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Hui","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da-Peng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,24]]},"reference":[{"issue":"6","key":"1989_CR1","doi-asserted-by":"publisher","first-page":"2557","DOI":"10.1007\/s10571-023-01336-6","volume":"43","author":"HQ Zhou","year":"2023","unstructured":"Zhou, H.Q., L.M. 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