Lipid Metabolism and Oxidative Stress in Uterine Corpus Endometrial Carcinoma: Prognostic and Immune Landscape Analysis

ABSTRACT Objective Uterine corpus endometrial carcinoma (UCEC) is a common gynecologic malignancy characterized by metabolic reprogramming and immune dysregulation. This study aimed to investigate the prognostic and diagnostic value of lipid metabolism‐ and oxidative stress–related genes (LMOSGs) in UCEC. Methods Transcriptomic and clinical data from The Cancer Genome Atlas and Gene Expression Omnibus were analyzed to identify differentially expressed LMOSGs associated with prognosis using univariate Cox regression. Molecular subtypes were defined by non‐negative matrix factorization (NMF) clustering. Functional differences between subtypes were evaluated through Gene Ontology/Kyoto Encyclopedia of Genes and Genomes enrichment, immune cell infiltration analysis, and tumor microenvironment scoring. Prognostic genes were further refined using Least Absolute Shrinkage and Selection Operator regression to construct a risk signature. Gene expression was validated by reverse transcription quantitative real‐time polymerase chain reaction, the Human Protein Atlas, and single‐cell RNA sequencing data. A diagnostic model was developed using 12 machine learning algorithms. In vitro functional assays were conducted to assess the effects of key LMOSGs on cell proliferation, migration, and invasion. Results Fifty‐nine LMOSGs were identified as significantly associated with prognosis. NMF clustering classified UCEC into two molecular subtypes with distinct immune landscapes and survival outcomes: Cluster 1 exhibited higher immune infiltration and a favorable prognosis, whereas Cluster 2 showed immune suppression and poorer survival. A robust 10‐gene prognostic signature (PHGDH, MAPT, KCNK9, EPHX2, LIPH, SLC8A1, CREB3L4, PDCD1, MYLIP, and ORMDL2) demonstrated strong predictive performance. Among these, EPHX2, SLC8A1, ORMDL2, and MYLIP showed superior diagnostic discrimination and were further validated functionally as key regulators of tumor progression. Conclusion LMOSGs play critical roles in UCEC heterogeneity, prognosis, and immune modulation. These genes represent promising biomarkers and potential targets for personalized therapeutic strategies. Trial Registration Not applicable.