Asymptomatic carotid artery stenosis (aCAS) increases the risk of ischemic stroke despite lacking clinical symptoms. This study sought to characterize the serum metabolic profile of aCAS and to identify potential biomarkers associated with plaque vulnerability by integrating metabolomics with radiomics. Untargeted metabolomic profiling was performed using liquid chromatography–tandem mass spectrometry (LC–MS/MS) on 72 participants, including 36 aCAS patients and 36 age- and sex-matched healthy controls (HC). Multivariate and univariate statistical analyses were conducted to screen differential metabolites. Candidate biomarkers were prioritized based on variable importance in projection (VIP) scores and random forest (RF) modeling. Plaque vulnerability features were quantified by high-resolution magnetic resonance vessel wall imaging (HR-VWI), and multi-omics analysis assessed associations between metabolites and plaque characteristics. A total of 144 significantly altered metabolites were identified between the aCAS and HC groups. Pathway enrichment analysis indicated that these differential metabolites were predominantly involved in lipid, purine, amino acid, nucleotide, and energy metabolism. Notably, 12R-HETrE, 9S-HOTrE, oleoylcarnitine, crichetocholic acid and 1β,3α,7α-trihydroxy-5β-cholan-24-oic acid—were significantly associated with radiomic markers of plaque vulnerability. This study delineates metabolic alterations in aCAS patients and identifies potential serum metabolic biomarkers associated with plaque vulnerability. Further validation is required.
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