Cellular Senescence Genes as Cutting-Edge Signatures for Abdominal Aortic Aneurysm Diagnosis: Potential for Innovative Therapeutic Interventions

Abdominal aortic aneurysm (AAA) is the most prevalent dilated arterial aneurysm that poses a significant threat to older adults, but the molecular mechanisms linking senescence to AAA progression remain poorly understood. This study aims to identify cellular senescence-related genes (SRGs) implicated in AAA development and assess their potential as therapeutic targets. Four hundred and twenty-nine differentially expressed genes (DEGs) were identified from the GSE57691 training set, and 867 SRGs were obtained. Through the intersection of DEGs with SRGs, 19 differentially expressed senescence-related genes (DESRGs) were uncovered. Functional enrichment analysis was performed to explore their biological roles in AAA. To identify hub genes, we applied machine learning algorithms, including LASSO, SVM-RFE and random forest. These hub genes were then validated in two independent datasets. In the initial validation cohort, significant differences in the expression levels of BTG2, ETS1, ID1 and ITPR3 were observed between the AAA and control groups. Receiver operating characteristic (ROC) analysis demonstrated a robust diagnostic performance. Further validation across different AAA stages (small, large and ruptured AAA) identified ETS1 and ITPR3 as potential diagnostic genes. Subsequently, the diagnostic relevance of ETS1 and ITPR3 was further validated in human serum samples and mouse models of AAA. In addition, single-cell RNA sequencing suggests that senescent endothelial cells play a pivotal role in AAA progression, we further confirmed the correlation between ETS1 and ITPR3 and senescent endothelial cells by WB, IF and RT-qPCR. In conclusion, our study reveals the pivotal role of cellular senescence in AAA progression and identifies ETS1 and ITPR3 as promising diagnostic biomarkers.