Integrative Single-Cell and Bulk Transcriptomic Analysis Reveals Ribosome Biogenesis-Associated Molecular Subtypes and Immune Characteristics in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) exhibits substantial molecular heterogeneity. We integrated single-cell and bulk transcriptomic data to investigate associations between ribosome biogenesis-related (RiboSis-related) gene expression and the molecular and immune characteristics of HCC. GLUL+ hepatocytes had the highest RiboSis-related gene-set score among hepatocyte subpopulations, and ligand–receptor analysis inferred an MDK–SDC2 interaction between ALDOA+ and GLUL+ hepatocytes. Feature selection identified four candidate genes, with subsequent subtype analysis highlighting BOP1 and EXOSC4. The two molecular subtypes differed in RiboSis-related gene expression, immune cell signature scores, mutation profiles, checkpoint gene expression, and TIDE scores. Immunohistochemistry showed higher BOP1 and EXOSC4 staining in HCC than in paired adjacent tissues. EXOSC4 staining was lower in HBV-associated than in non-viral HCC within the tissue microarray. These findings associate RiboSis-related expression with distinct molecular and inferred immune features in HCC. The clinical relevance of these subtypes for immunotherapy and the functional roles of BOP1 and EXOSC4 require further validation.