Hepatitis B virus (HBV) integration is strongly associated with hepatocellular carcinoma (HCC). However, the genetic alterations and pathogenesis mechanisms remain significantly unexplored, especially for HBV-inserted cancer-related genes. This study identified recurrent HBV DNA integration into the CCDC91 gene in HCC tissues (n = 17) using pooled analysis and HBV capture sequencing. CCDC91 expression was positively correlated with HBV DNA presence, and higher levels were linked to shorter overall survival in HCC patients. CCDC91 was upregulated in HCC and promoted HCC malignancy in vitro and in vivo. CCDC91 deficiency increased sensitivity to sorafenib treatment. By RNA sequencing and co-immunoprecipitation assays, we further demonstrated that the Ct-HBx upregulated CCDC91 and that CCDC91 induced aerobic glycolysis by activating LDHA to drive HCC progression. In conclusion, the HBV integrated gene CCDC91 is a novel HCC-related gene that functions through the Ct-HBx/CCDC91/LDHA axis. Our work sheds light on the mechanism in driving HCC progression and sorafenib resistance.© 2025. The Author(s).