Integrative epidemiological analysis, plasma metabolomics, and single-cell RNA sequencing reveal the protective effects and mechanisms of dietary flavonoids against abdominal aortic aneurysm.

Abstract

Although flavonoids have been shown to have various health benefits, their association with abdominal aortic aneurysm (AAA) and the underlying mechanisms remain unclear. This study included 188 101 UK Biobank participants who were free of AAA at baseline dietary assessment. Multivariable Cox proportional hazards models were used to analyze the association between flavonoid intake and AAA risk, and elastic net regression was applied to construct a metabolite signature to evaluate potential mediation effects. Additionally, network pharmacology integrated with single-cell RNA sequencing (scRNA-seq) was used to further explore the mechanism of flavonoids against AAA development. Compared with the lowest quartile, the highest quartile of proanthocyanidin intake was associated with a 29% lower risk of AAA. If proanthocyanidin intake in the population was increased from the lowest to the highest quartile, approximately 17.24% of new AAA cases could be prevented. We further identified a metabolic signature consisting of 28 metabolites that was associated with proanthocyanidin intake. Mediation analysis showed that this metabolic signature explained 14.57% of the association between proanthocyanidins intake and AAA risk, with inflammation-related metabolites playing a major role. Network pharmacology combined with scRNA-seq analysis revealed that the preventive effect of proanthocyanidins on AAA may result from their regulation of the C-type lectin receptor signaling pathway in macrophages, with CLEC4E being the most differentially expressed member of the C-type lectin family. These findings support a protective role of proanthocyanidins in AAA and indicate that CLEC4E may be an important potential target for its protective action.