Integrative Multi-Omics and Single-Cell Analysis Prioritizes YWHAB Within Ubiquitination-Related Transcriptional Programs in Endometrial Carcinoma

Background: Ubiquitination-related transcriptional programs may help characterize epithelial heterogeneity in endometrial carcinoma (EC). We aimed to identify candidates associated with these programs and epithelial plasticity. Methods: We integrated a 43,613-cell atlas from five endometrioid EC samples and two normal endometrial samples with bulk transcriptomic, genetic-association and protein-expression data. Five scoring methods defined a consensus expression score, with HIGH and LOW quartiles defined within the Epithelial + EMT_like lineage. Differential expression and high-dimensional weighted gene co-expression network analysis (hdWGCNA) identified candidates for exploratory Mendelian randomization (MR) and survival-based prioritization among 541 patients from The Cancer Genome Atlas Uterine Corpus Endometrial Carcinoma (TCGA-UCEC) cohort. Repeated nested cross-validation and cross-model feature support were used to evaluate internal performance and candidate stability. Pseudobulk, independently curated ubiquitin–proteasome system (UPS) gene sets and scSurv input masking provided sensitivity analyses. Results: The lineage-restricted screen identified 444 candidates, including 412 detectable in TCGA. GeneCards and curated Reactome and KEGG UCell scores were positively correlated (ρ = 0.519 and 0.579). YWHAB ranked fourth among 412 genes in the top-10% workflow analysis and fifth in the top-20% sensitivity analysis. Among the 12 nominal MR-associated genes, it had the highest machine-learning priority. Its single-nucleotide polymorphism (SNP) MR estimate was nominal (odds ratio (OR) = 1.732, p = 0.0488) and did not survive multiple-testing correction. Higher bulk YWHAB expression was associated with poorer overall survival (HR = 2.188, 95% CI 1.559–3.072). Western blotting showed higher YWHAB protein expression in EC than controls (nine versus nine tissues, p = 0.0027), consistent with descriptive Human Protein Atlas (HPA) staining. Single-cell analyses associated YWHAB with RNA processing, proteostasis-related expression and epithelial-state heterogeneity. Conclusions: Lineage-restricted discovery and cross-model prioritization identify YWHAB as an exploratory candidate associated with ubiquitination-related transcriptional programs in EC. Protein-expression evidence supports its further investigation, while causal function and clinical prognostic utility require independent validation.