Abstract

Background Hepatocellular carcinoma (HCC) is an aggressive cancer with limited therapies. Although transposable element–derived genes are increasingly linked to tumorigenesis, the role of the TIGD family in HCC remains unclear. This study examined the expression, clinical significance, and stemness-related features of TIGDs in HCC, emphasizing their prognostic and therapeutic potential. Method TIGD expression was analyzed using TCGA data via GEPIA2, cBioPortal, and Kaplan–Meier Plotter, with protein validation from the Human Protein Atlas. Single-cell RNA-seq data (GSE242889) were used to examine TIGD expression across hepatic cell types. Survival and Cox regression analyses assessed prognostic value, while functional enrichment and immune infiltration analyses explored biological roles. TIGD5-high and TIGD5-low epithelial subsets were compared for functional features and cell–cell communication. Results TIGD1, 3, 4, 5, 6, and 7 were significantly upregulated in HCC. High TIGD4, TIGD5, and TIGD6 expression correlated with poorer overall survival and served as independent prognostic markers. TIGD5 exhibited the broadest and highest expression across immune and stromal compartments. Stratification of epithelial cells into TIGD5-high and TIGD5-low subsets revealed distinct functional phenotypes: TIGD5-high cells showed enrichment in extracellular matrix organization, growth factor signaling, and immune regulatory pathways, with enhanced communication probability within the tumor microenvironment. Notably, TIGD5+ epithelial cells demonstrated increased interaction strength and MIF signaling pathway engagement compared to TIGD5- counterparts. Functional analyses indicated roles in RNA splicing, DNA replication, and cell-cycle regulation. TIGDs also showed associations with immune infiltration, particularly Th2 cells. Conclusion TIGD4, TIGD5, and TIGD6 exhibit oncogenic potential and may serve as prognostic biomarkers and therapeutic targets in HCC. Their stem-cell–assoc