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The mechanisms underlying these events are incomprehensible and therefore therapeutic opportunities are limited. Although drugs have been showing some promise in TBI outcome, the restoration of BBB damage remain elusive. Thymosin \u03b24 (T\u03b24) is a secreted 43 amino acid peptide showed beneficial outcome in cerebral ischemia or TBI, however, it\u2019s role in hypoxia-induced BBB damage remains elusive. We hypothesize that T\u03b24 protect hypoxia-induced BBB disruption via Sphingosine 1\u2013phosphate receptor 1 (S1PR1) modulation. In the current study, we investigated the beneficial effects of T\u03b24 in hypoxia induced gene expression of several tight junction proteins, S1PR1, endothelial cell permeability and tight junction dynamics in human brain microvascular endothelial cells (hBMVECs), one of the important cell types in the BBB integrity. The data suggests that pretreatment with T\u03b24 reversed the hypoxia-induced damage of BBB components in hBMVECs. Furthermore, results identify S1PR1, a possible target for T\u03b24. Inhibition of S1PR1 showed that T\u03b24 failed to offer protection. Together, data provided evidence that S1PR1 is pivotal and T\u03b24 can serve as a protective agent in BBB integrity and may offer a promising therapeutic target. In conclusion, we propose that depletion of S1PR1signaling is vital in hypoxia-induced BBB pathophysiology and T\u03b24 may be tested as a potential treatment modality and warrant further investigation.<\/jats:p>","DOI":"10.1038\/s41598-025-28435-2","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T14:15:51Z","timestamp":1764598551000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Thymosin \u03b24 stabilizes hypoxia induced brain microvascular endothelial cell dysfunction through S1PR1 dependent mechanisms"],"prefix":"10.1038","volume":"15","author":[{"given":"William G.","family":"Stewart","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina D.","family":"Hejl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rakeshwar S.","family":"Guleria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudhiranjan","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,1]]},"reference":[{"key":"28435_CR1","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.nbd.2009.07.030","volume":"37","author":"NJ Abbott","year":"2010","unstructured":"Abbott, N. 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