Long non-coding RNAs (lncRNAs) are a class of RNAs that do not code protein but play important roles in diverse biological processes.In recent years,with the application of high-throughput sequencing,a great deal of lncRNAs associated with virus infections have been discovered and intensively studied,but there are few studies about the relationship between lncRNAs and HCV replication.Previous studies show that signal transducer and activator of transcription 3 (STAT3)is activated by HCV and in turn increases the replication of HCV.However,the detailed molecular mechanism is still only partially understood.In the present study,we have established that phosphorylated STAT3 can promote the HCV replication.Furthermore,we identify that several lncRNAs can be up-regulate and down-regulated by phosphorylated STAT3 by using human PCR array method.And among these lncRNAs,lnc-Lethe was involved in the HCV replication.Transfection of siRNA Lethe partially blocked the replication of HCV in Huh7 cells.Data also indicated that when transfected with siRNA Lethe,the expression levels of PKR,OAS and IRF1,which were all ISGs,were all up regulated.Based on our findings from Lethe knockdown,we have identified that Lethe,which was upregulated by activated STAT3,may promoting the replication of HCV through a negative regulatory mechanism of type I IFN response.