Navigating liver cancer with mouse models: a comprehensive overview of HCC experimental systems

Hepatocellular carcinoma (HCC) is the most prevalent primary hepatic malignancy and is globally the third leading cause of cancerrelated deaths. Despite significant advancements in diagnostic techniques and therapeutic interventions, HCC prognosis remains poor due to asymptomatic progression, frequent recurrence, and inadequate treatment responsiveness. The development of HCC is closely linked to chronic liver diseases, such as hepatitis B and C infections, alcoholic liver disease, and metabolic dysfunctionassociated steatotic liver disease (MASLD). To better understand hepatocarcinogenesis and support therapeutic development, a range of animal models have been established. Among these animal models, mice are extensively utilized because of their genetic manipulability, physiological resemblance to humans, and relatively short experimental timelines. The most well-established protocol for analyzing the onset and progression of HCC is the diethylnitrosamine (DEN)-induced HCC model. Additionally, carbon tetrachloride (CCl₄)-induced HCC models, DEN+CCl₄ combination HCC models, MASLD HCC mouse models (STAM™), alcoholassociated HCC models, hydrodynamics-based transfection systems, and orthotopic HCC transplantation approaches also provide distinct advantages for exploring specific elements of HCC pathophysiology. Unfortunately, due to the complexity and heterogeneity of human HCC, no single animal model can accurately recapitulate the disease. Therefore, careful selection or combination of appropriate mouse models for specific research objectives is crucial to enhance the translational value of preclinical studies. This review provides a comprehensive overview of the mouse models currently employed in HCC research, highlighting their respective strengths and limitations. Such understanding and application of these HCC models are essential for advancing mechanistic insights and fostering the development of novel therapeutic strategies.