Integrated UPLC-MS/MS Metabolomics Reveals Novel Metabolic Markers for Type I Endometrial Carcinogenesis in Clinical Samples

Objective This study aimed to identify differential metabolites between type I endometrial cancer (EC) and normal tissues (NT) using untargeted metabolomics based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). We further explored key metabolites and metabolic pathways to underpin clinical diagnosis and treatment. Methods Paired cancerous and normal endometrial tissues were collected from 30 type I EC patients between June 2022 and October 2023. Metabolite profiling was performed using UPLC-MS/MS. Differential metabolites were screened using multivariate statistical analysis (OPLS-DA) combined with t-tests, with thresholds set at VIP > 1 and P < 0.05. Pathway enrichment analysis was conducted using KEGG database, and transcriptomic data from GEO database (GSE196033) from the GEO database were integrated to correlate differentially expressed genes (DEGs, |FC| >1.5, P  < 0.05) with metabolic alterations. Results A total of 1,093 metabolites were detected, with amino acids (33.12%) and fatty acids (13.45%) being the dominant classes. OPLS-DA revealed significant metabolic disparities between EC and NT. We identified 436 differential metabolites, including 382 upregulated (e.g., salidroside, 3-oxodecanoic acid, dehydroepiandrosterone) and 54 downregulated (e.g., Δ12-prostaglandin J2, 2,3-dihydroxybenzoic acid) compounds. KEGG pathway analysis highlighted 166 perturbed pathways, including glycerophospholipid metabolism, ABC transporters, amino acid biosynthesis, and ferroptosis. Integration with transcriptomics data identified 11 differentially expressed genes (DEGs), of which 7 genes (e.g., pkm,, alc7A5 ) being upregulated and 4 genes (e.g., lama4, nr2f1 ) being downregulated. Conclusion Our research underscored the pivotal roles of ABC transporters and ferroptosis in regulating EC progression. By integrating metabolomic and transcriptomic data, we gained novel insights into the pathogenesis of EC and identified candidate biomarkers for potential therapeutic intervention.