UCP2 is identified as a therapeutic target for abdominal aortic aneurysm by comprehensive bioinformatic analysis and experimental validation.

Abdominal aortic aneurysm (AAA) is a potentially life-threatening vascular condition that currently lacks effective pharmacological treatment. The disease is strongly associated with chronic inflammation, where immune cells like macrophages play a crucial role. Efferocytosis, the process by which apoptotic cells are cleared, is involved in regulating inflammation. However, the role of efferocytosis in AAA pathogenesis remains largely unexplored. A combination of bioinformatic analysis and experimental validation was employed to investigate the role of efferocytosis-related genes (EFRGs) in AAA pathogenesis. Differentially expressed efferocytosis-related genes (EFRDEGs) were identified using datasets such as GSE47472, GSE57691 and GSE7084. Machine learning techniques, including LASSO, Random Forest and XGBoost were used to identify key biomarkers. Single-cell RNA sequencing were used to explore the interactions between EFRGs and immune cells within the AAA microenvironment. Furthermore, the expression of UCP2 was validated in both human and mouse AAA tissues, and pharmacological inhibition of UCP2 was tested in elastase-induced AAA mouse models. The analysis identified 15 EFRDEGs associated with AAA. Machine learning methods identified UCP2, DUSP5, and IL1B as key diagnostic biomarkers, with the highest predictive accuracy (AUC of 1). Single-cell RNA sequencing revealed that UCP2 is highly expressed in macrophages within AAA tissue compared to controls. Moreover, UCP2 was significantly upregulated in both human AAA specimens and elastase-induced mouse AAA models. Immunofluorescence staining confirmed the colocalization of UCP2 with the macrophage marker F4/80 in AAA lesions. Pharmacological inhibition of UCP2 with Genipin significantly attenuated AAA progression in mice, reducing aortic dilation. This study offers a comprehensive exploration of efferocytosis-related genes in AAA and highlights UCP2 as a potential therapeutic target, providing novel strategies for medical intervention.