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Background:  Diabetic retinopathy (DR) is a major diabetes-related disease linked to metabolism. However, the cognition of metabolic pathway alterations in DR remains scarce. We aimed to corroborate alterations of metabolic pathways identified in prior studies and investigate novel metabolic dysregulations that may lead to new prevention and treatment strategies for DR.   Methods:  In this case-control study, we tested 613 serum metabolites in 69 pairs of type 2 diabetic patients (T2DM) with DR and propensity score-matched T2DM without DR  via  ultra-performance liquid chromatography-tandem mass spectrometry system. Metabolic pathway dysregulation in DR was thoroughly investigated by metabolic pathway analysis, chemical similarity enrichment analysis (ChemRICH), and integrated pathway analysis. The associations of ChemRICH-screened key metabolites with DR were further estimated with restricted cubic spline analyses.   Results:  A total of 89 differentially expressed metabolites were identified by paired univariate analysis and partial least squares discriminant analysis. We corroborated biosynthesis of unsaturated fatty acids, glycine, serine and threonine metabolism, glutamate and cysteine-related pathways, and nucleotide-related pathways were significantly perturbed in DR, which were identified in prior studies. We also found some novel metabolic alterations associated with DR, including the disturbance of thiamine metabolism and tryptophan metabolism, decreased trehalose, and increased choline and indole derivatives in DR.   Conclusions:  The results suggest that the metabolism disorder in DR can be better understood through integrating multiple biological knowledge databases. The progression of DR is associated with the disturbance of thiamine metabolism and tryptophan metabolism, decreased trehalose, and increased choline and indole derivatives.

High-Coverage Serum Metabolomics Reveals Metabolic Pathway Dysregulation in Diabetic Retinopathy: A Propensity Score-Matched Study