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We previously identified endothelial cells (ECs) as a primary site of IRE1 pathway activation following brain injury. In this study, we investigated the role of endothelial IRE1 signaling in TBI using EC-specific IRE1 conditional knockout mice subjected to cortical ablation. Loss of IRE1 in ECs exacerbated blood-brain barrier (BBB) disruption, enhanced immune cell infiltration, amplified neuroinflammation, and expanded neuronal damage, ultimately leading to worsened neurological outcomes. RNA-sequencing revealed enrichment of interferon-related programs and identified Cxcl10 as an endothelial chemokine linked to the exacerbated leukocyte recruitment in endothelial IRE1 deficiency. Treatment with the chemical chaperone tauroursodeoxycholic acid (TUDCA) suppressed Cxcl10 expression both in vitro and in vivo, and significantly improved motor function following TBI. These findings reveal a critical role for endothelial IRE1 signaling in maintaining BBB integrity and restraining inflammation during the acute phase of TBI. Modulation of ER stress in brain ECs may represent a promising and accessible therapeutic strategy for reducing secondary injury after TBI.<\/jats:p>","DOI":"10.1038\/s41419-026-08461-2","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T09:24:24Z","timestamp":1770629064000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Endothelial IRE1 signaling maintains blood\u2013brain barrier integrity and limits neuroinflammation after traumatic brain injury"],"prefix":"10.1038","volume":"17","author":[{"given":"Qiyan","family":"Fan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2113-0707","authenticated-orcid":false,"given":"Mika","family":"Takarada-Iemata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loc Dinh","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nahoko","family":"Okitani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"RongRong","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Tamatani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Ishii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsuyoshi","family":"Hattori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0413-7816","authenticated-orcid":false,"given":"Hiroyasu","family":"Kidoya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6672-4122","authenticated-orcid":false,"given":"Yoshiaki","family":"Kubota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takao","family":"Iwawaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osamu","family":"Hori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,9]]},"reference":[{"key":"8461_CR1","doi-asserted-by":"publisher","first-page":"1004","DOI":"10.1016\/S1474-4422(22)00309-X","volume":"21","author":"AIR Maas","year":"2022","unstructured":"Maas AIR, Menon DK, Manley GT, Abrams M, \u00c5kerlund C, Andelic N, et al. 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