Background/aims:Our previous reports, both experimental and human studies, have shown the novel geneKCTD9 contributed to liver injurythrough hepatic NK cell activation in HBV induced acute-on-chronic liver failure.This study aims to elucidate the therapeutic role of KCTD9 in a mice model.Methods: murine hepatitis virus strain 3 (MHV-3) induced fulminant viral hepatitis (MHV-3-FVH) mice model was adopted in the study.The mouse KCTD9(mKCTD9) expression plasmid and anshRNA plasmid specifically targeting this molecule were constructed and introduced into infected mice by hydrodynamic delivery.The expression of KCTD9 as well as function of hepatic NK cells was detected, respectively.Results:The results showed abundant expression of KCTD9 in hepatic NK cells from mice with MHV-3 infection.TheshRNA significantly inhibited KCTD9 expression in hepatic NK cells with decreased CD69 expression, cytotoxicity andameliorated MHV-3-FVHin these micedemonstratingas an increased survival, improved liver functions and histopathology manifestation.In contrast, delivery of the KCTD9 expression plasmid to MHV-3-infected mice led to a profound progression of liver disease.Conclusion:Our study further elaborated the novel KCTD9 gene contributes to liver injury through NK cell activation in virus-induced liver failure, while interference targeting KCTD9 gene could ameliorated the disease, which provide a potential therapeutic target for virus induced liver failure.