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Hepatitis C virus (HCV) hijacks host lipid metabolism for its infection.However, this mechanism remains poorly understood.We previously reported that HCV replication requires hepatocyte nuclear factor 4α (HNF4α), a regulator of very-low-density lipoprotein-mediated lipid transport in the liver, and peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), a regulator of energy metabolism.This study showed that HNF4α and wild-type PGC-1α (WT-PGC-1α)/liver-specific PGC-1α (L-PGC-1α) have combinatorial effects on HCV production.Cell death-inducing DFFA-like effector B (CiDeB) is an important regulator of various lipid metabolic pathways.We found that CiDeB was induced by HCV infection in a PGC-1α-and HNF4α-dependent manner.In turn CiDeB was also required for HCV production, particularly in the post-entry steps of the HCV life cycle.WT-PGC-1α/L-PGC-1α together with HNF4α regulated HCV production partially through CiDeB.Furthermore, our results demonstrated that CiDeB interacted with HCV NS5A and NS2 proteins.Yeast two-hybrid analysis showed that the N-terminus of CiDeB and the domain Ⅱ of NS5A were indispensable for CiDeB-NS5A interaction.Remarkably, we showed that CiDeB was also required for dengue virus production.Collectively, CiDeB, which is regulated by PGC-1α and HNF4α, participates in the post-entry steps of HCV life cycle and interacts with HCV NS5A.Combined with our previous studies that HCV induced PGC-1α and HNF4α expression, these results suggest that HCV hijacks PGC-1 α and HNF4α, as well as the downstream factor CiDeB, for HCV production.Thus, PGC-1 α, HNF4α, and CiDeB are potential drug targets for anti-HCV therapy.