• CSTF2 expression is upregulated in immune-reactive and inactive carrier phases of chronic HBV infection, correlating with reduced viral replication.
• Overexpression of CSTF2 attenuates HBV DNA and protein levels without affecting HBV RNA levels, indicating a post-transcriptional regulatory mechanism.
• CSTF2 relocalizes to the cytoplasm upon HBV transfection and interacts with the HBV PRE, impeding nuclear export of HBV RNA.
• Distinct functional domains of CSTF2 exhibit varying antiviral efficacies, highlighting a multifaceted host defense mechanism and potential therapeutic target.