De Matteis S, Ghetti M, Gramantieri L, et al. - Through several distinct mechanisms, hepatitis B- and C-virus (HBV and HCV) infections contribute to hepatocellular carcinoma (HCC) development. In addition to a diverse molecular background, disparities are also observed in the metabolic profiles in the HCC subtypes, indicating the possible necessity of integration of multiple different approaches in prevention and treatment. In this study, the response of two HCC cell lines representative of different virus-related etiology, namely Hep3B (HBV+) and HUH7 (permissive to HCV replication), to sorafenib treatment was analyzed. Per outcomes, treatment response in HCC is influenced by virus-related specificities, along with molecular, metabolic and microenvironmental factors. This emphasizes the necessity for considering these differences in the design of future clinical trial aimed to improve HCC patients’ outcome.