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Much is known about the damage to the blood\u2013brain barrier (BBB) in response to hypoxia. Studies have shown that endothelial cell death is closely linked to functional impairment of BBB. Mounting evidences have demonstrated that ferroptosis, a new pathway regulating cell death, is implicated in brain injury. However, whether ferroptosis is involved in hypoxia\u2010induced BBB disruption remains ambiguous. Here, we utilized in vivo zebrafish and in vitro bEnd.3 cells to explore the correlation between endothelial ferroptosis and hypoxia\u2010induced BBB damage. We found that hypoxic treatment for 45\u2009min can induce BBB disruption by triggering down\u2010regulation of claudin\u20105 (CLDN5) both in zebrafish cerebrovascluar endothelial cells and bEnd.3 cells. Besides, in vitro and in vivo studies revealed the cysteine\/glutamate antiporter xCT (also known as solute carrier family 7 member 11; SLC7A11) decrease, glutathione peroxidase 4 (GPX4) and glutathione (GSH) reduction, 4\u2010Hydroxynonenal (4\u2010HNE) increasement, malondialdehyde (MDA) upregulation and reactive oxygen species (ROS) accumulation in hypoxia group. Further mechanism studies indicated that hypoxia\u2010induced BBB damage might associate with microvascular endothelial cellular ferroptosis, since hypoxic exposure significantly activated the expression of ferroptosis\u2010related genes (\n                    <jats:italic>Ptgs2<\/jats:italic>\n                    ,\n                    <jats:italic>Por<\/jats:italic>\n                    ,\n                    <jats:italic>Lpcat3<\/jats:italic>\n                    ,\n                    <jats:italic>Alox5<\/jats:italic>\n                    ,\n                    <jats:italic>Alox12<\/jats:italic>\n                    ,\n                    <jats:italic>Nfe2l2,<\/jats:italic>\n                    and\n                    <jats:italic>Ncoa4<\/jats:italic>\n                    ) and inhibited the expression of\n                    <jats:italic>Slc7a11<\/jats:italic>\n                    . Additionally, the application of 20\u2009\u03bcM ferrostatin\u20101 (Fer\u20101), a ferroptosis inhibitor, could partially alleviate BBB disruption under hypoxia, suggesting that inhibition of ferroptosis might be a potential strategy for some neurological diseases with BBB defect.\n                  <\/jats:p>","DOI":"10.1096\/fj.202201765r","type":"journal-article","created":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T12:14:12Z","timestamp":1681301652000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Ferroptosis of brain microvascular endothelial cells contributes to hypoxia\u2010induced blood\u2013brain barrier injury"],"prefix":"10.1096","volume":"37","author":[{"given":"Qiuling","family":"Liu","sequence":"first","affiliation":[{"name":"Affiliated Hospital of Guangdong Medical University &amp; Zhanjiang Key Laboratory of Zebrafish Model for Development and Disease Guangdong Medical University  Zhanjiang China"},{"name":"The Marine Biomedical Research Institute of Zhanjiang Guangdong  Zhanjiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tujing","family":"Song","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Guangdong Medical University &amp; Zhanjiang Key Laboratory of Zebrafish Model for Development and Disease Guangdong Medical University  Zhanjiang China"},{"name":"The Marine Biomedical Research Institute of Zhanjiang Guangdong  Zhanjiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Chen","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Guangdong Medical University &amp; Zhanjiang Key Laboratory of Zebrafish Model for Development and Disease Guangdong Medical University  Zhanjiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Guangdong Medical University &amp; Zhanjiang Key Laboratory of Zebrafish Model for Development and Disease Guangdong Medical University  Zhanjiang China"},{"name":"The Marine Biomedical Research Institute of Zhanjiang Guangdong  Zhanjiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7530-199X","authenticated-orcid":false,"given":"Wen","family":"Li","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Guangdong Medical University &amp; Zhanjiang Key Laboratory of Zebrafish Model for Development and Disease Guangdong Medical University  Zhanjiang China"},{"name":"Department of Pediatrics Affiliated Hospital of Guangdong Medical University  Zhanjiang 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