DOI: 10.1097/ot9.0000000000000149 ISSN: 2095-9621

Pan-cancer analysis combined with single-cell profiling reveals epigenetic and immune associations of ADH4 in hepatocellular carcinoma

Zhifeng Zhao, Xichi Chen, Xuejiao Chen, Bin Hu, Yuliang Tu, Kai Jiang, Hongbo Huan
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Background:

Alcohol dehydrogenase 4 (ADH4) is an important enzyme involved in ethanol and retinol metabolism. Although altered ADH4 expression has been reported in several malignancies and has been suggested to have diagnostic or prognostic value, its broader significance across cancer types remains unclear. In particular, the potential relationship between ADH4 and the immune microenvironment in hepatocellular carcinoma (HCC) has not been fully addressed.

Methods:

To clarify these issues, transcriptomic data from the Cancer Genome Atlas, Genotype-Tissue Expression, and Gene Expression Omnibus were analyzed to characterize ADH4 expression patterns in multiple cancers. Associations with clinical parameters were examined to assess prognostic relevance. Genes that correlated with ADH4 were subjected to enrichment analysis to explore their underlying biological processes. DNA methylation data were evaluated using MEXPRESS, and their relationship with immune infiltration was investigated using Tumor–Immune System Interactions and Drug Bank. In addition, single-cell RNA sequencing data from the tumor immune single-cell hub 2 were analyzed to determine the cellular distribution of ADH4 in HCC and to further examine immune-related gene expression at the single-cell level.

Results:

ADH4 expression was significantly reduced in 22 cancer types, a finding supported by independent Gene Expression Omnibus cohorts and immunohistochemical validation using the Human Protein Atlas. In HCC, decreased ADH4 expression was independently associated with poorer overall survival ( p < 0.001) and showed good prognostic prediction (area under the curve = 0.894). Enrichment analyses indicated that ADH4-related genes were mainly involved in retinol and lipid metabolic processes. Several cytosine–phosphate–guanine methylation sites were negatively correlated with ADH4 expression and linked to variations in immune cell infiltration. Notably, ADH4 methylation was associated with chemokines and their receptors, immune regulatory factors, and antigen-presenting factors. Single-cell analysis demonstrated that ADH4 is primarily expressed in malignant hepatocytes, whereas chemokines and checkpoint-related genes are predominantly detected in immune cell populations, suggesting a potential link between ADH4 dysregulation and immune remodeling in HCC.

Conclusions:

These findings suggest that ADH4 may serve as a prognostic biomarker in liver cancer and may function as a tumor suppressor. Integrative analyses further indicated that ADH4 may influence HCC progression through metabolic pathways and interactions with the tumor immune environment, providing a basis for future mechanistic studies and potential therapeutic exploration.

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