Caffeine restricts hepatitis B virus transcription by inhibiting γ-H2AX formation

The influence of caffeine on human health has been widely studied, but its relevance to hepatitis B virus (HBV) remains unclear. Here, we report that exogenous caffeine suppresses HBV RNA and core protein expression in hepatoma cells. Mechanistically, caffeine reduces the DNA damage marker <i>γ</i>-H2AX, which in turn diminishes HBV transcription. Functional assays revealed that <i>γ</i>-H2AX enhances HBV core promoter activity by facilitating the recruitment of peroxisome proliferator-activated receptor-<i>α</i> (PPARα). Chromatin immunoprecipitation confirmed that reduced <i>γ</i>-H2AX levels impair the binding of PPARα to the HBV core promoter. These findings establish a <i>γ</i>-H2AX-PPARα signaling axis that promotes HBV transcription and demonstrate that caffeine interferes with this pathway. In summary, our study demonstrated that <i>γ</i>-H2AX may serve as a nutritionally targetable node, supporting dietary and adjunct strategies for HBV management.