Plasma Exosome Metabolomics Reveal Stage‐Specific Alterations in Elderly Women With Premetabolic and Metabolic Syndrome

ABSTRACT Background Metabolic syndrome (MetS) is a chronic disorder that poses a major threat to global health. Exosomes have emerged as promising biomarkers for diagnosing and monitoring chronic diseases. However, stage‐specific alterations in the exosomal metabolome during MetS development remain poorly understood. This study aimed to characterize the plasma exosomal metabolome and explore candidate exosomal biomarkers in individuals with MetS. Methods This study included 20 patients with MetS, 23 individuals with pre‐MetS, and 45 healthy controls. Plasma exosomes were isolated and analyzed using untargeted liquid chromatography‐mass spectrometry‐based metabolomics. Differential metabolites were defined by a dual‐threshold, that is, p < 0.05 from t ‐test and variable importance in projection > 1 from partial least squares discriminant analysis, with fold change indicating their expression changes. Further, we employed machine learning algorithms to predict MetS status. Results We identified 27 differential metabolites between the pre‐MetS and control groups, mainly enriched in histidine metabolism and the tricarboxylic acid cycle. Of these, 12 metabolites were upregulated, and 15 were downregulated, with 1‐methylhistidine and isocitrate playing central regulatory roles. Comparison between the MetS and control groups revealed 45 differentially expressed metabolites, mainly enriched in thiamine metabolism, including 13 upregulated and 32 downregulated. In the pre‐MetS group, cladribine showed the highest area under the curve (AUC) (0.743, p < 0.05), whereas 3‐methylxanthine yielded the largest AUC (0.714, p < 0.05) in the MetS group. Conclusion Our study characterized stage‐dependent alterations in the plasma exosome‐derived metabolome in MetS and suggests that exosomal metabolomics may provide complementary molecular information on early MetS metabolic perturbations.