Integrative genetic analyses for drug repurposing identify emodin as a candidate modulator of STAT3 signaling in abdominal aortic aneurysm.

Abstract

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease lacking effective pharmacological therapies. To identify potential therapeutic targets and candidate compounds, we performed integrative genetic analyses for drug repurposing by combining Mendelian randomization (MR), summary-data-based Mendelian randomization (SMR), and Bayesian colocalization. This framework prioritized multiple druggable candidates, among which STAT3 emerged as a key regulatory node. Subsequent functional studies demonstrated that emodin suppressed vascular smooth muscle cell proliferation, migration, phenotypic switching, and inflammatory responses. These effects were accompanied by reduced STAT3 phosphorylation and nuclear localization. Molecular docking suggested a potential binding mode of emodin within the STAT3 SH2 domain, while cellular thermal shift assays demonstrated thermal stabilization of STAT3 by emodin in intact cells, consistent with target engagement. Notably, emodin and the selective STAT3 inhibitor STAT3-IN-13 produced comparable effects, and co-treatment did not yield additive efficacy, suggesting overlapping mechanisms. In vivo, emodin attenuated aneurysm development and reduced vascular inflammation in experimental models. Collectively, these findings identify emodin as a candidate modulator of AAA progression acting through suppression of STAT3-associated signaling pathways, and demonstrate the potential of genetic evidence-guided drug repurposing strategies in complex vascular diseases.