Icariin alleviates abdominal aortic aneurysm by targeting CYP1B1 to inhibit M1 polarization and VSMC apoptosis.

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease with limited medical therapies. The role and targets of icariin, a flavonoid from Epimedium brevicornu Maxim, in AAA remain unclear. First, transcriptomic data from the GEO dataset GSE183464 were analyzed to screen differentially expressed genes (DEGs). DEGs were then integrated with M1 polarizationrelated genes (GeneCards) and icariin-targeted genes (CTD/SwissTargetPrediction) using Venn analysis, and the obtained candidate genes were subjected to GO and KEGG enrichment analyses. Machine learning (LASSO and Random Forest) was employed to prioritize core targets from a gene expression matrix, followed by molecular docking (AutoDock Vina) for assessing the binding affinity between icariin and Cytochrome P450 Family 1 Subfamily B Member 1 (CYP1B1), and visualizing (PyMOL and Discovery Studio) the binding modes. The effects of icariin were evaluated in THP-1-derived macrophages. Bioinformatics identified 15 candidate genes; machine learning converged on CYP1B1/BCL2L11. Molecular docking confirmed icariin's high affinity for CYP1B1. Icariin dose-dependently inhibited LPS/IFN-γ-induced M1 polarization and NF-κB activation, while CYP1B1 overexpression reversed these effects. Icariin also reduced M1-induced VSMC apoptosis. By demonstrating that icariin alleviates AAA by targeting CYP1B1 to suppress NF-κB-driven M1 polarization and VSMC apoptosis, this study establishes the icariin-CYP1B1 axis as a promising therapeutic strategy.