Etiology-Driven Mouse Models of Hepatocellular Carcinoma: Paving the Way for Precision Oncology.

Background: Hepatocellular carcinoma (HCC) is biologically heterogeneous, and its genomic alterations, inflammatory context, and tumor immune microenvironment are strongly shaped by the underlying etiology, including chronic hepatitis B virus (HBV) infection, metabolic dysfunction-associated steatotic liver disease (MASLD), and alcohol exposure. This etiological diversity complicates the selection and interpretation of preclinical models. Genetically engineered mouse models (GEMMs), particularly when combined with dietary, chemical, viral, or alcohol-related insults, provide useful systems for dissecting how defined genetic drivers interact with disease-specific liver environments in an immunocompetent host. Main Body: This review summarizes etiology-aligned GEMMs and related mouse models for HCC. In HBV-related models, we discuss how viral antigen exposure, HBV-associated genomic instability, Short Conclusion: Etiology-aligned GEMMs can help match biological questions to appropriate preclinical platforms and generate testable hypotheses about therapy response. However, etiology alone should not be treated as a substitute for molecular profiling or clinical validation. Future models should integrate precise genetic engineering with fibrotic or cirrhotic backgrounds, microbiome-aware environmental modulation, and complementary human-relevant systems to better capture the complex evolution of human HCC.