Genetic and epidemiological evidence suggests an association between ulcerative colitis (UC) and liver hepatocellular carcinoma (LIHC). However, whether UC-related transcriptional programs are linked to LIHC prognosis and tumor immune–metabolic phenotypes remains unclear. UC-associated genes (UCGs) were identified by integrating three UC transcriptomic datasets (GSE75214, GSE92415, and GSE87466; 64 normal and 347 UC samples) using weighted gene co-expression network analysis and differential expression analysis. Diagnostic performance was evaluated using ROC analysis. Unsupervised clustering was performed to characterize UC heterogeneity. In TCGA-LIHC, we constructed a quantitative UC score by principal component analysis based on the prognosis-related genes derived from UC-score-associated differentially expressed genes, and assessed its associations with overall survival, immune infiltration (ssGSEA), and immunotherapy-related signatures (TIDE). Hub genes were further examined by single-cell annotation (GSE290925) and in vitro assays. Eighteen UCGs were identified in UC and stratified UC samples into three molecular clusters with distinct immune and metabolic features. In LIHC, a UC score derived from the UCG-related program robustly stratified overall survival in TCGA-LIHC and was externally validated in GSE76427, with the low-score group showing a more favorable prognosis and distinct immune-infiltration patterns. The UC score was also associated with differences in immunotherapy-related signatures, suggesting potential relevance to immune escape phenotypes. Among candidate hub genes, MEP1B and HSD3B2 showed high diagnostic accuracy for UC (pooled AUC = 0.936 and 0.923, respectively) and were downregulated in LIHC tumors. Single-cell analysis indicated relatively higher MEP1B expression in the B-cell compartment. In a UC-like in vitro inflammatory model, MEP1B and HSD3B2 downregulation was validated. The overexpression of MEP1B or HSD3B2 attenuated malignant behaviors of hepatocellular carcinoma cells. The UC score captures UC-related immune–metabolic programs that are associated with prognosis and tumor immune phenotypes in LIHC. MEP1B and HSD3B2 represent UC-linked markers with tumor-suppressive effects in HCC cell models, providing a rationale for further mechanistic studies on gut–liver axis-related comorbidity.
Chang et al. (2026) studied this question.