We next examined the effect of silencing human NTCP on HBV and HDV infections in human hepatocytes. Human hepatoma cell line HepaRG is the only cell line known to date to be susceptible to HBV and HDV infections upon differentiation into a mixture of hepatocyte-like and biliary-like cells (Gripon et al., 2002) . HepaRG differentiation requires a lengthy cell culture procedure, including maintaining undifferentiated cells for 2 weeks before induction, followed by induction with corticoids and DMSO for another 2-4 weeks (Gripon et al., 2002) . The NTCP mRNA level was low in HepaRG cells before induction when examined on days 5 and 10 after initial plating, but increased dramatically when the cells differentiated after induction (Figure 4B, . To examine if the acquired hNTCP expression on differentiated HepaRG cells is required for HDV and HBV infections, the cells were transfected with siRNAs targeting hNTCP. About 70% HDV infection was reduced by hNTCP knockdown as indicated by decreased levels of HDV viral RNAs ( Figure 4B , upper-right). Similarly, HBV infection was also inhibited as indicated by significantly reduced HBeAg at multiple time points ( Figure 4B , lower-left), as well as viral RNAs including the 3.5 kb RNA for HBV pre-C and pregenome RNA (pgRNA) and HBV total RNA ( Figure 4B , lower-right) quantified at the end of the experiment. We further validated the critical role of hNTCP on HBV infection in PHHs, the natural host of the virus. Consistently, knockdown of hNTCP significantly reduced HBV infection, which was correlated with the NTCP mRNA knockdown efficiency. Both viral antigens and viral RNAs were decreased in cells transfected with hNTCP-specific siRNAs but not with the control siRNA ( Figure 4C ). Taken together, these data demonstrate NTCP as a common key cellular receptor component necessary for HBV and HDV infections of hepatocytes.