This study investigates the role of SPI1 in the pathogenesis of intracranial aneurysm (IA). 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.
RobbaCBuslKMClaassenJ, et al. Contemporary management of aneurysmal subarachnoid haemorrhage. An update for the intensivist. Intensive Care Med2024; 50(5): 646–664.
3.
HutchinsonHRezkRFaragM, et al. Molecular targets for intracranial aneurysm treatment. Int J Mol Sci2025; 26(20): 10053.
4.
Méndez-BarberoNGutiérrez-MuñozCBlanco-ColioLM.Cellular crosstalk between endothelial and smooth muscle cells in vascular wall remodeling. Int J Mol Sci2021; 22(14): 7284.
5.
CampbellJHCampbellGR.Endothelial cell influences on vascular smooth muscle phenotype. Annu Rev Physiol1986; 48: 295–306.
6.
YuGLiJZhangH, et al. Single-cell analysis reveals the implication of vascular endothelial cell-intrinsic ANGPT2 in human intracranial aneurysm. Cardiovasc Res2025; 121(4): 658–673.
7.
SheinbergDLMcCarthyDJElwardanyO, et al. Endothelial dysfunction in cerebral aneurysms. Neurosurg Focus2019; 47(1):E3.
8.
TexakalidisPSweidAMouchtourisN, et al. Aneurysm formation, growth, and rupture: the biology and physics of cerebral aneurysms. World Neurosurg2019; 130: 277–284.
9.
ZhangYXinLXiangM, et al. The molecular mechanisms of ferroptosis and its role in cardiovascular disease. Biomed Pharmacother2022; 145: 112423.
10.
ZhangFLiKZhangW, et al. Ganglioside GM3 protects against abdominal aortic aneurysm by suppressing ferroptosis. Circulation2024; 149(11): 843–859.
11.
SunDYWuWBWuJJ, et al. Pro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence. Nat Commun2024; 15(1): 1429.
12.
LiSZhangQChenZ, et al. Novel insight into ferroptosis-related genes, molecular subtypes, and immune characteristics in intracranial aneurysms. Inflamm Res2022; 71(10–11): 1347–1364.
13.
FangGTianYYouL, et al. KLF15 prevents ferroptosis in vascular smooth muscle cells via interacting with p53. Biochem Biophys Res Commun2025; 770: 152029.
14.
ZhuHTanJWangZ, et al. Bioinformatics analysis constructs potential ferroptosis-related ceRNA network involved in the formation of intracranial aneurysm. Front Cell Neurosci2022; 16: 1016682.
15.
ZhangHZhouSSunM, et al. Ferroptosis of endothelial cells in vascular diseases. Nutrients2022; 14(21): 4506.
16.
XiangPChenQChenL, et al. Metabolite Neu5Ac triggers SLC3A2 degradation promoting vascular endothelial ferroptosis and aggravates atherosclerosis progression in ApoE(−/−)mice. Theranostics2023; 13(14): 4993–5016.
17.
LiuJPangSYZhouSY, et al. Lipocalin-2 aggravates blood-brain barrier dysfunction after intravenous thrombolysis by promoting endothelial cell ferroptosis via regulating the HMGB1/Nrf2/HO-1 pathway. Redox Biol2024; 76: 103342.
18.
LiZBuYWangC, et al. Extracellular vesicle-packaged GBP2 from macrophages aggravates sepsis-induced acute lung injury by promoting ferroptosis in pulmonary vascular endothelial cells. Redox Biol2025; 82: 103614.
19.
De SmedtJvan OsEATalonI, et al. PU.1 drives specification of pluripotent stem cell-derived endothelial cells to LSEC-like cells. Cell Death Dis2021; 12(1): 84.
20.
RenJXiaoXLiR, et al. Single-cell sequencing reveals that endothelial cells, EndMT cells and mural cells contribute to the pathogenesis of cavernous malformations. Exp Mol Med2023; 55(3): 628–642.
21.
YangLJuHChenZ, et al. PU.1 aggravates hepatic sinusoidal obstruction syndrome by upregulating PTBP1 and activating the Wnt/β-catenin pathway. Histol Histopathol2025; 1: 18949.
22.
ZhangQLiuHZhangM, et al. Identification of co-expressed central genes and transcription factors in atherosclerosis-related intracranial aneurysm. Front Neurol2023; 14: 1055456.
23.
ZhaoHLiSTZhuJ, et al. Analysis of peripheral blood cells’ transcriptome in patients with subarachnoid hemorrhage from ruptured aneurysm reveals potential biomarkers. World Neurosurg2019; 129:e16-e22.
24.
ChenTGeRBaiJ, et al. SPI1 transcriptional activates TXNRD1 to protect trophoblast cell from ferroptosis. Reprod Sci2025; 32(9): 3103–3114.
25.
ZhaoFTianHWangY, et al. LINC01004-SPI1 axis-activated SIGLEC9 in tumor-associated macrophages induces radioresistance and the formation of immunosuppressive tumor microenvironment in esophageal squamous cell carcinoma. Cancer Immunol Immunother2023; 72(6): 1835–1851.
26.
ChenYLinBYangS, et al. IRF1 suppresses colon cancer proliferation by reducing SPI1-mediated transcriptional activation of GPX4 and promoting ferroptosis. Exp Cell Res2023; 431(1): 113733.
27.
BirnhuberABiasinVSchnoeglD, et al. Transcription factor Fra-2 and its emerging role in matrix deposition, proliferation and inflammation in chronic lung diseases. Cell Signal2019; 64: 109408.
28.
WangHSugimotoKLuH, et al. HDAC1-mediated deacetylation of HIF1α prevents atherosclerosis progression by promoting miR-224-3p-mediated inhibition of FOSL2. Mol Ther Nucleic Acids2021; 23: 577–591.
29.
WanXGuanSHouY, et al. FOSL2 promotes VEGF-independent angiogenesis by transcriptionnally activating Wnt5a in breast cancer-associated fibroblasts. Theranostics2021; 11(10): 4975–4991.
30.
ChenHWangLLiuJ, et al. LncRNA ITGB2-AS1 promotes cisplatin resistance of non-small cell lung cancer by inhibiting ferroptosis via activating the FOSL2/NAMPT axis. Cancer Biol Ther2023; 24(1): 2223377.
31.
LiuNYinWYDuanWQ, et al. HTB50-2 inhibits growth and migration of triple-negative breast cancer via FOSL2/FOXC1 signaling axis and subsequent ferroptosis. Curr Med Chem2024; 32(32): 7082–7099.
KubraKGadduGKLiongueC, et al. Phylogenetic and expression analysis of FOS transcription factors in zebrafish. Int J Mol Sci2022; 23(17): 10098.
34.
YuJGuiXZouY, et al. A proteogenomic analysis of cervical cancer reveals therapeutic and biological insights. Nat Commun2024; 15(1): 10114.
35.
NukiYTsouTLKuriharaC, et al. Elastase-induced intracranial aneurysms in hypertensive mice. Hypertension2009; 54(6): 1337–1344.
36.
MakinoHTadaYWadaK, et al. Pharmacological stabilization of intracranial aneurysms in mice: a feasibility study. Stroke2012; 43(9): 2450–2456.
37.
LiuYZhengDZhaoL, et al. SPI1 suppresses YAP phosphorylation in vascular endothelial cells to prevent intracranial aneurysm progression. Neurochem Int2026; 192: 106100.
38.
PierotLGawlitzaMSoizeS.Unruptured intracranial aneurysms: management strategy and current endovascular treatment options. Expert Rev Neurother2017; 17(10): 977–986.
39.
KanekoNTateshimaS.Future of cerebral aneurysm treatment. No Shinkei Geka2021; 49(1): 164–169.
40.
QuKMoSHuangJ, et al. SPI1-KLF1/LYL1 axis regulates lineage commitment during endothelial-to-hematopoietic transition from human pluripotent stem cells. iScience2024; 27(8): 110409.
41.
XuYLiuXChenH, et al. Spi1 aggravates neuropathic pain by modulating Clec7a-mediated neuroinflammation and microglial phagocytosis. J Headache Pain2025; 26(1): 158.
42.
YangGLiFHuX, et al. Exploration of the role and mechanism of Rhizoma Paridis total saponins in osteosarcoma based on SPI1/LCN2-mediated ferroptosis. Front Oncol2025; 15: 1592862.
43.
LiRYuLXuM, et al. Androgen receptor governs tip cell formation in cerebrovascular malformations. Circ Res2025; 137(5): 628–645.
44.
XueWDengL.EP300 improves endothelial injury and mitochondrial dysfunction in coronary artery disease by regulating histone acetylation of SOCS1 promoter via inhibiting JAK/STAT pathway. Cytokine2024; 176: 156507.
45.
CaiQZhaoQYangQ, et al. The Ku protein family regulates hyperglycemia-induced vascular endothelial cell inflammation by modulating P300 levels. Exp Cell Res2025; 444(2): 114399.
46.
ShiJWangQHWeiX, et al. Histone acetyltransferase P300 deficiency promotes ferroptosis of vascular smooth muscle cells by activating the HIF-1α/HMOX1 axis. Mol Med2023; 29(1): 91.
47.
LiuCShenYCavdarO, et al. Angiotensin II-induced vascular endothelial cells ferroptosis via P53-ALOX12 signal axis. Clin Exp Hypertens2023; 45(1): 2180019.
48.
XuXXuXZhouW, et al. ALDH4A1 knockdown inhibits in vitro atherosclerosis model by modulating Trim28-mediated P53 ubiquitination to suppress ferroptosis of vascular endothelial cells. In Vitro Cell Dev Biol Anim2025; 61(9): 1110–1119.
49.
MaXHuangYHeX, et al. Endothelial cell-derived let-7c-induced TLR7 activation on smooth muscle cell mediate vascular wall remodeling in Moyamoya disease. Transl Stroke Res2023; 14(4): 608–623.
50.
LuoYTangHZhangZ, et al. Pharmacological inhibition of epidermal growth factor receptor attenuates intracranial aneurysm formation by modulating the phenotype of vascular smooth muscle cells. CNS Neurosci Ther2022; 28(1): 64–76.
51.
ZhengDLiuJPiaoH, et al. ROS-triggered endothelial cell death mechanisms: Focus on pyroptosis, parthanatos, and ferroptosis. Front Immunol2022; 13: 1039241.
52.
XuXXuXDMaMQ, et al. The mechanisms of ferroptosis and its role in atherosclerosis. Biomed Pharmacother2024; 171: 116112.
53.
YuFDuanYLiuC, et al. Extracellular vesicles in atherosclerosis and vascular calcification: the versatile non-coding RNAs from endothelial cells and vascular smooth muscle cells. Front Med (Lausanne)2023; 10: 1193660.
54.
FisherCLDemelSL.Nonsteroidal anti-inflammatory drugs: a potential pharmacological treatment for intracranial aneurysm. Cerebrovasc Dis Extra2019; 9(1): 31–45.
55.
DuanJZhaoQHeZ, et al. Current understanding of macrophages in intracranial aneurysm: relevant etiological manifestations, signaling modulation and therapeutic strategies. Front Immunol2023; 14: 1320098.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
