Systematic transcriptomic analysis of UDP-glucuronosyltransferases reveals UGT2B11 as a diagnostic and metabolic marker in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is characterized by profound metabolic reprogramming and immune heterogeneity, yet transcriptomic markers that reflect tumor-specific metabolic states remain limited. UDP-glucuronosyltransferases (UGTs) are key hepatic enzymes involved in detoxification and glucuronidation, but their systematic transcriptional landscape and clinical relevance in HCC have not been comprehensively explored. Here, we performed a comprehensive multi-cohort transcriptomic analysis of all 19 functional UGT family genes across TCGA-LIHC, GepLiver, GEPIA3, HCCDB, and an independent institutional cohort. Across datasets, most UGT genes exhibited global transcriptional downregulation with minimal genomic alterations, indicating that dysregulated expression rather than structural variation predominates in HCC. Among them, UGT2B11 uniquely demonstrated consistent upregulation, a markedly higher proportion of high-expression cases, and reproducible diagnostic performance across multiple cohorts. In the GepLiver and institutional cohorts, UGT2B11 expression was significantly elevated in HCC compared with normal and adjacent liver tissues, yielding area-under-the-curve values ranging from 0.79 to 0.84. Pathway enrichment analyses of genes correlated with UGT2B11 revealed strong enrichment of glucuronidation-related pathways, consistent with canonical UGT function, while also identifying mTORC1 signaling as a recurrent transcriptional feature modestly associated with UGT2B11 expression. Single-cell RNA-sequencing analyses demonstrated that UGT2B11 expression is largely confined to malignant hepatocyte populations, supporting its tumor-specific transcriptional activation. In parallel, immune infiltration analyses revealed significant positive associations between UGT2B11 expression and multiple immune cell signatures, most prominently Tregs, further supported by correlations with established Treg-associated genes. Collectively, this study delineates the transcriptomic landscape of the UGT family in HCC and identifies UGT2B11 as a tumor-associated metabolic transcript with reproducible diagnostic potential, while showing modest associations with mTORC1-related transcriptional programs and immune features.