Hepatitis E virus (HEV) causes hepatitis that can resolve on its own. However, the disease can progress to fulminant or even chronic hepatitis in some patients. Several genotypes of HEV exist, including human-restricted ones, such as HEV-1, and zoonotic ones such as HEV-3. Swine are the main reservoir of zoonotic HEV that causes asymptomatic infection in this host, suggesting that this species can control efficiently HEV-3. Recently, we have identified a panel of interferon-stimulated genes (ISGs) whose expression is upregulated in human hepatic cells (HepaRG) and pig livers upon HEV-3 infection. In this study, we addressed the anti- or pro- viral activity of these candidate ISGs. To achieve this goal, we produced lentiviral vectors to overexpress these ISGs of interest from different species (human, macaque and swine) in the bipotent HepaRG cell line before infection with HEV-3f. We have monitored transduction level through reporter gene expression (RFP) by flow cytometry, as well as the amount of HEV-3f genome copies by RT-qPCR. For some of the overexpressed ISGs, RFP signal was maintained at high level (up to 80%) for up to 35 days, while others show low expression or were toxic. This method has allowed us to identify several ISGs able to interfere with HEV replication, including some that have already been described in the literature, such as RIG-I and MDA5. These results confirm the relevance of our model in an infectious context. We are currently investigating their mode of action and assessing potential differences in their antiviral activity among various species and HEV genotypes. Overall, this work will highlight the effector functions of the IFN response activated during HEV infection and how this response might influence inter-species transmission of HEV.