Integrated Bioinformatics and Multi-Omics Analysis of ZBTB40 Expression, Prognostic Relevance, and Regulatory Networks in Hepatocellular Carcinoma

Background and Objectives: Identifying regulatory genes that integrate epigenetic, transcriptional, immune, and non-coding RNA networks may improve prognostic stratification in hepatocellular carcinoma (HCC). ZBTB40 is a poorly characterized transcription factor whose clinical relevance and multi-layered regulatory role in HCC remain unclear. This study systematically investigated the prognostic significance, molecular regulatory networks, and toxicogenomic interactions of ZBTB40 in HCC. Materials and Methods: Comprehensive multi-omics analyses were conducted utilizing TCGA-HCC datasets and various public bioinformatics platforms. We systematically evaluated ZBTB40 expression patterns, survival outcomes, clinicopathological associations, DNA methylation status, immune cell infiltration, and competing endogenous RNA (ceRNA) networks. Additionally, chemical–gene interactions were analyzed using the Comparative Toxicogenomics Database (CTD). Results: ZBTB40 was significantly overexpressed in HCC, closely correlating with advanced clinicopathological features and poor survival outcomes. This upregulation was significantly associated with promoter hypomethylation. Furthermore, ZBTB40 expression was associated with specific immune infiltration patterns. A ZBTB40-centered ceRNA network identified key regulatory miRNAs, including miR-24-3p, miR-34a-5p, miR-132-3p, and miR-222-3p, along with prognostically relevant lncRNAs and circRNAs. CTD analysis identified 39 key chemical modulators of ZBTB40 (e.g., sorafenib, aflatoxin B1) and revealed RNF13 and CHD3 as functionally related genes sharing substantial chemical interaction profiles. Functional analyses suggested ZBTB40’s involvement in chromatin remodeling, the cell cycle, and immune-related pathways. Conclusions: ZBTB40 expression is associated with multi-layered molecular features involving epigenetic, post-transcriptional, immune-related, and toxicogenomic signatures in HCC.