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Results confirmed that SPI1 was significantly upregulated in both an in vivo mouse IA model and an in vitro model of angiotensin II-stimulated human cerebral microvascular endothelial cells. Functional studies demonstrated that SPI1 overexpression promoted vascular endothelial cell ferroptosis, as evidenced by dysregulation of key markers (p53, GPX4, SLC7A11, ACSL4, TFRC), elevated lipid peroxidation, and mitochondrial damage, whereas SPI1 knockdown attenuated these effects. Mechanistically, SPI1 upregulated the histone acetyltransferase EP300, which subsequently mediated the acetylation of FOSL2. Acetylated FOSL2 enhanced the transcriptional activity of the p53 promoter, thereby driving the execution of ferroptosis. In a co-culture system, SPI1-induced vascular endothelial ferroptosis facilitated the phenotypic switching of vascular smooth muscle cells towards a synthetic phenotype. Crucially, administration of the SPI1 inhibitor DB2313 effectively suppressed the SPI1\/EP300\/FOSL2 axis, inhibited vascular endothelial ferroptosis, mitigated vascular smooth muscle cell phenotypic switching, and alleviated IA progression in mice. Our findings revealed a novel SPI1\/EP300\/FOSL2 acetylation axis that promoted vascular endothelial ferroptosis and vascular smooth muscle cell dysfunction in IA, identifying SPI1 as a promising therapeutic target for the condition.<\/jats:p>","DOI":"10.1177\/0271678x261463947","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T03:58:32Z","timestamp":1781755112000},"page":"2739-2756","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["SPI1 promotes endothelial cell ferroptosis and intracranial aneurysm progression via EP300-mediated FOSL2 acetylation"],"prefix":"10.1177","volume":"46","author":[{"given":"Lingfeng","family":"Lai","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhifan","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hengyang","family":"Ouyan","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5869-6739","authenticated-orcid":false,"given":"Yeyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,7,5]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2016.150"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-024-07387-7"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms262010053"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22147284"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.ph.48.030186.001455"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvae186"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.3171\/2019.4.FOCUS19221"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.wneu.2019.07.093"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2021.112423"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.123.066110"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-54088-2"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00011-022-01633-8"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2025.152029"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2022.1016682"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.3390\/nu14214506"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.87968"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2024.103342"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2025.103614"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-03356-2"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-023-00962-w"},{"key":"e_1_3_4_22_2","first-page":"18949","article-title":"PU.1 aggravates hepatic sinusoidal obstruction syndrome by upregulating PTBP1 and activating the Wnt\/\u03b2-catenin pathway","volume":"1","author":"Yang L","year":"2025","unstructured":"Yang L, Ju H, Chen Z, et al. 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