Targeting Mitochondrial and Inflammatory Pathways in Abdominal Aortic Aneurysm: Discovery of Sigma-1 and PPAR-γ Agonists through Plasma MicroRNA Profiling

Background/aim: Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease marked by progressive aortic dilation, high rupture-associated mortality, and a complete lack of effective pharmacological therapies. Because microRNAs (miRNAs) are key regulators of vascular inflammation, extracellular matrix remodeling, and smooth muscle cell function, they represent highly promising therapeutic targets. The aim of this study was to employ an integrative systems biology framework to identify novel miRNA-drug regulatory axes for AAA intervention. Materials and methods: AAA transcriptome data were integrated with experimentally validated miRNA–mRNA interactions to prioritize candidate miRNAs. A total of 22 previously unreported miRNAs were selected for further analysis. Their expression levels were validated using RT-qPCR in a cross-sectional study of 30 AAA patients and 15 healthy controls. Additionally, drug repositioning analysis was performed to identify compounds targeting genes regulated by the validated miRNAs. Results: RT-qPCR validation confirmed significant dysregulation of nine circulating miRNAs. Subsequent drug repositioning analysis identified 41 candidate compounds targeting the genes regulated by these miRNAs. Notably, 23 of these agents had no prior association with AAA, highlighting their translational potential. Sigma-1 receptor (S1R) agonists, PPAR-γ agonists, and MAPK pathway inhibitors emerged as promising therapeutic candidates; however, their biological relevance and therapeutic potential remain to be experimentally validated. These novel candidates converge on mitochondrial, inflammatory, and oxidative stress pathways central to aneurysm progression. Conclusion: This study provides a comprehensive, miRNA-guided pharmacological framework for AAA, highlighting novel and therapeutic opportunities. The candidates identified offer translational potential for the development of nonsurgical treatment strategies for AAA.