<p>The incidence of intracranial aneurysms (IAs) is markedly elevated in postmenopausal women compared to men and premenopausal women, a disparity historically linked to declining estrogen levels. Emerging evidence, however, suggests that the expression and functional roles of estrogen receptors (ERs), including ERα, ERβ, and GPER1, in vascular tissues may implicate estrogen-independent pathways in vascular aging and related pathologies. An integrative bioinformatics approach, combining three IA datasets (GSE75436, GSE122897, GSE54083) and two vascular endothelial cell senescence (VECS) datasets (GSE214476, GSE102397) from the Gene Expression Omnibus (GEO) database, was employed to investigate this hypothesis and define shared molecular mechanisms. This cross-disease differential expression analysis identified 452 significantly downregulated genes, suggesting conserved pathogenic pathways in IA and VECS. Among ERs, GPER1 was uniquely downregulated in both conditions. Subsequent weighted gene co-expression network analysis and subsequent module clustering revealed ACACB as a hub gene co-expressed with GPER1 and inversely correlated with IA and VECS progression. In vitro validation confirmed that GPER1 expression was reduced during VECS and that GPER1 silencing decreased ACACB expression and accelerated endothelial senescence, supporting its estrogen-independent role in vascular homeostasis. Computational pharmacological screening further identified PD0325901, SCH772984, and selumetinib as potential therapeutic agents targeting both GPER1 and ACACB, offering a dual-pathway therapeutic strategy. The identification of GPER1 and ACACB as potential target genes associated with IA and VECS provides a framework for developing therapies that circumvent hormone dependency, addressing an unmet need in the treatment of IA and age-related vascular pathologies.</p>