An immunocompetent murine model of virus-elicited liver fibrosis and hepatocellular carcinoma

Background & Aims Hepatocellular carcinoma (HCC) is the third deadliest cancer worldwide. Over 75% of HCC cases are associated with chronic viral infections. Mechanistic studies and preclinical therapeutic development for virus-associated HCC have been limited by a paucity of small animal models of chronic hepatotropic virus infection that faithfully recapitulate human disease. Methods We investigated chronic viral infection with Norway rat hepacivirus (NrHV) – a virus closely related to HCV – in immunocompetent laboratory mice. We assessed the development of chronic hepatitis, progressive liver fibrosis, and HCC. Liver tumors were histologically and molecularly characterized, and liver transcriptomes were analyzed to compare NrHV-induced changes with those observed in human HCV-associated disease. Results Chronic NrHV infection induced persistent hepatitis, progressive liver fibrosis, and HCC in immunocompetent mice. NrHV-elicited tumors closely resembled HCV-associated tumors. Transcriptome analyses revealed numerous similarities between chronic NrHV infection in mice and HCV infection in humans, including changes in pathways associated with fibrosis, inflammation, and oncogenesis. Conclusions These findings establish an experimentally tractable, physiologically relevant, and immunocompetent mouse model of virus-elicited progressive liver fibrosis and oncogenesis. Impact and implications The Norway rat hepacivirus-induced hepatocellular carcinoma model represents the first immunocompetent infectious system that faithfully recapitulates the multistage progression from chronic viral hepatitis to spontaneous hepatocellular carcinoma, bridging a long-standing translational gap between mechanistic mouse studies and human liver cancer. By mirroring the immunopathological, molecular, and sex-associated features of chronic HCV infection, this model provides an unparalleled platform to investigate virus-host interactions underlying fibrosis and oncogenesis. High hepatocellular carcinoma incidence and the genetically tractable C57BL/6 background further enhance experimental utility, enabling precise mechanistic dissection and genetic manipulation in a physiologically relevant setting. The capacity to study spontaneous tumor development in the context of natural infection allows for rigorous testing of antifibrotic and anti-cancer strategies, while the persistence of oncogenic potential after viral clearance raises important questions about irreversible disease reprogramming and elevated cancer risk following viral cure – issues of direct relevance to patients cured of HCV.