Hepatitis Viruses Infection Up-Regulating Fibrosis Signals in Hepatocellular Carcinoma.

Background and Objectives: In Taiwan, hepatitis B virus (HBV) or hepatitis C virus (HCV) infections are the most common causes of hepatocellular carcinoma (HCC). However, an increasing number of non-HBV and non-HCV (NBNC) patients developing HCC has been noted in recent years. The pathogenic connection between NBNC status and HCC development remains largely elusive. This study aims to explore the differences in clinical manifestations and pathological findings among HCC patients with HBV, HCV, and NBNC etiologies. Methods: This retrospective study analyzed 521 HCC patients with complete hepatic viral profiles at a single medical center in Taiwan between 2016 and 2020. Differentially expressed gene (DEG) analysis, xCell stromal cell estimation, and Gene Set Enrichment Analysis (GSEA) were employed to explore the distinct oncogenic mechanisms between the viral and NBNC groups. Results: The final cohort included 38 NBNC-HCC patients. Clinically, the NBNC-HCC patients exhibited a significantly lower FIB-4 index than the HCV-HCC patients (3.191 vs. 6.077, p = 0.0019). Furthermore, fewer NBNC-HCC patients presented with imaging-defined cirrhosis compared to HBV-HCC patients (44.4% vs. 68.1%, p = 0.0057), and a lower proportion had high Ishak scores (5-6) compared to HCV-HCC patients (31.3% vs. 75.6%, p = 0.0025). DEG analysis revealed differential expression in oncogenes (OIT3, AKR1B10) and liver fibrosis-related genes (COLEC10, CXCL14, and LINC01093). Subsequent GSEA and stromal cell analyses highlighted significant differential enrichment in hepatic stellate cells and vascular endothelial cells. Conclusions: NBNC-HCC patients present with significantly lower rates of cirrhosis and fibrosis compared to their viral counterparts. The distinct gene expression profiles and cell-type enrichment features observed between the viral and NBNC groups indicate a divergent, etiology-specific pathogenesis driving NBNC-HCC.