Abstract Body: Ascending thoracic aortic aneurysms (ATAA) are potentially fatal conditions marked by progressive enlargement of the ascending aorta, with risks of dissection or rupture if untreated. Identifying reliable biomarkers and understanding the cellular drivers of disease are critical for targeted therapy development. We conducted a comprehensive characterization of ATAA tissue using advanced imaging, single-cell transcriptomics, and plasma proteomics. From June 2022 to October 2023, 12 patients (92% male, median age 57) undergoing aortic surgery were recruited. Our single-cell RNA-seq (scRNA-seq) analysis identified 26 distinct cell populations, including subtypes of macrophages, T cells, endothelial cells, fibroblasts, and vascular smooth muscle cells (VSMCs). Surprisingly, we found no significant differences in cell proportions or major differentially expressed genes between aneurysm and control tissues, contrary to earlier reports. By integrating public scRNA-seq datasets, we confirmed some previously reported findings, though major disparities remained, particularly in cell population proportions. Plasma proteomics revealed several biomarkers—IL8, CCL11, FGF-23, HGF, TNF, CASP-8, NT-3, TWEAK, and ADA—with marginal correlations to aortic diameter. To support these findings, analysis of the UK Biobank plasma proteome atlas showed a significant association between FGF-23 and TAA (OR = 1.35, 95% CI = [1.09-1.68], p = 6.24×10-3) in a cohort of 49,601 patients. FGFR1, the receptor for FGF-23, was predominantly expressed in fibroblast and VSMC subsets, indicating its potential role in modulating the behavior of these cell types. Taken together, these findings provide new insights into the complex cellular and molecular landscape of ATAA, highlighting potential therapeutic targets and biomarkers for assessing disease severity and risk.