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Uremic pruritus (UP) is a prevalent complication of uremia, severely affecting the quality of life of patients. The abnormal and accumulation of metabolites in the circulatory system of UP patients may constitute a significant inducer of pruritus. However, a systematic evaluation of the differences in serum metabolomic profiles among UP patients with different etiologies has yet to be reported. This study collected serum samples from 18 pruritic uremia patients from DKD, HN, and GN, as well as 18 non-pruritic uremia patients, respectively, to conduct a metabolomic analysis. The aim was to identify variations in metabolomic profiles and potential biomarker metabolites among pruritic patients of different etiologies. The results revealed a total of 4575 metabolites, with 256 and 172 differentially expressed metabolites (DEMs) (upregulated and downregulated) in the DKDUP vs. Neg comparison group, 303/202 in the HNUP vs. Neg comparison group, and 217/170 in the GNUP vs. Neg comparison group. The DEMs primarily involved metabolic pathways such as tyrosine metabolism, fatty acid biosynthesis, and unsaturated fatty acid synthesis. A cross-analysis of the three comparison groups identified 77 common DEMs, among which the TOP 10 primarily included esters, oleic acid esters, and glycerides, all significantly elevated in UP. Moreover, ROC analysis identified potential biomarkers with the highest AUC value of 0.972 in all three comparison groups. The data from this study provide critical insights into the metabolomics of pruritic uremic patients, assisting in both the understanding of disease mechanisms and the development of therapeutic interventions.