Single-Cell Transcriptomics of Pyrimidine Salvage in HBV-Related HCC Reveals Prognostic and Immune Infiltration Features.

Hepatocellular carcinoma (HCC) is primarily caused by hepatitis B virus (HBV). The pyrimidine-salvage pathway (PSP) is crucial for tumor proliferation, but its prognostic and immunomodulatory roles in HBV-HCC are unclear. By using single-cell transcriptomics, we investigated PSP signatures and their link to clinical outcomes and immune modulation in HBV-HCC. Data from XENA and GEO databases were analyzed. Malignant cell subpopulations were identified, and single-cell PSP activity was quantified. HBV-specific malignant subpopulations were characterized using the Ro/e metric. Cell-cell communication was analyzed. A prognostic model was developed and validated using a training cohort, and a nomogram was constructed. Immune infiltration, drug sensitivity, and the functional role of ferritin light chain (FTL) were examined experimentally. Malignant cells were classified into HBV⁻ and HBV⁺ subpopulations. The HBV⁺ group showed low PSP gene (PSPG) expression. The six-gene prognostic model demonstrated high predictive accuracy for 1-, 3-, and 5-year survival. High-risk patients had shorter survival and increased infiltration of macrophages, Tregs, and activated dendritic cells. Drug sensitivity analysis identified potential agents. In vitro, FTL silencing suppressed HBV-HCC cell proliferation and migration. This investigation clarified the prognostic significance of PSPGs and their immunomodulatory roles in HBV-HCC, and established a prognostic model with predictive power. FTL, identified as a key gene, represented a potential therapeutic target for HBV-HCC. These findings provided a novel theoretical foundation for the treatment of HBV-HCC.