Cross-etiology transcriptomic conservation in hepatocellular carcinoma reveals opposing proliferation and hepatocyte-loss programs validated across cohorts

2026 · doi:10.64898/2026.03.10.710938
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Abstract

Background Hepatocellular carcinoma (HCC) arises from diverse etiologies, but the balance between conserved and specific transcriptomic programs remains unclear.

Methods

HBV and HCV cohorts were analyzed using GSVA to quantify Hallmark shifts. Biology was distilled into proliferation (ProlifHub) and hepatocyte-loss (HepLoss) modules, forming a composite HCCStateScore. An HBV injury axis was adjusted for proliferative state (E2F/G2M). Validation was performed using GSE14520 and GEPIA3.

Results

Hallmark analysis revealed conserved proliferative activation and hepatocyte function suppression across etiologies. In HBV-HCC, the injury axis remained significantly elevated after adjusting for proliferation (p≈0.0147), indicating an injury component independent of the cell cycle. HCCStateScore robustly separated tumor from non-tumor tissue (AUC≈0.986, p=0). GEPIA3 confirmed concordant expression and survival associations for module genes.

Conclusions

HCC features conserved opposing proliferation and hepatocyte-loss programs. HBV-associated tumors retain a distinct injury-linked component not fully explained by cell division. This validated score provides a framework for cross-cohort analysis and mechanistic prioritization in liver cancer research. Competing Interest Statement The authors have declared no competing interest.

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last seen: 2026-05-20T01:45:00.602351+00:00