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Herein, we aimed to determine the role of glutamine in MMD pathogenesis, and 360 adult patients were prospectively enrolled. Human brain microvascular endothelial cells (HBMECs) were subjected to Integrin Subunit Beta 4 (ITGB4) overexpression or knockdown and atorvastatin. We assessed factors associated with various signaling pathways in the context of the endothelial\u2010to\u2010mesenchymal transition (EndMT), and the expression level of related proteins was validated in the superficial temporal arteries of patients. We found glutamine levels were positively associated with a greater risk of stroke (OR\u00a0=\u00a01.599, <jats:italic>p<\/jats:italic>\u00a0=\u00a00.022). After treatment with glutamine, HBMECs exhibited enhanced proliferation, migration, and EndMT, all reversed by ITGB4 knockdown. In ITGB4\u2010transfected HBMECs, the MAPK\u2013ERK\u2013TGF\u2013\u03b2\/BMP pathway was activated, with Smad4 knockdown reversing the EndMT. Furthermore, atorvastatin suppressed the EndMT by inhibiting Smad1\/5 phosphorylation and promoting Smad4 ubiquitination in ITGB4\u2010transfected HBMECs. We also found the protein level of ITGB4 was upregulated in the superficial temporal arteries of patients with MMD. In conclusion, our study suggests that glutamine may be an independent risk factor for hemorrhage or infarction in patients with MMD and targeting ITGB4 could potentially be therapeutic approaches for MMD.<\/jats:p>","DOI":"10.1002\/mco2.525","type":"journal-article","created":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T15:30:15Z","timestamp":1713195015000},"source":"Crossref","is-referenced-by-count":13,"title":["High glutamine increases stroke risk by inducing the endothelial\u2010to\u2010mesenchymal transition in moyamoya disease"],"prefix":"10.1002","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6715-298X","authenticated-orcid":false,"given":"Qiheng","family":"He","sequence":"first","affiliation":[{"name":"Department of Neurosurgery Beijing Tiantan Hospital, Capital Medical University Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junsheng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of 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