LAUSR

ABSTRACT Chronic hepatitis B virus (HBV) infection remains a serious global health concern. Cisplatin is a chemotherapeutic agent commonly used to treat various cancers. However, HBV‐infected patients receiving chemotherapy are at risk of HBV reactivation via unknown mechanisms, which we aimed to elucidate in this study. We found that autophagy plays a central role in cisplatin‐induced HBV replication. Cisplatin treatment induced autophagy in both HBV‐replicating cells and an HBV‐transgenic mouse model as evident from marked upregulation of microtubule‐associated protein 1 light chain 3 (LC3)‐II and the accumulation of red fluorescent protein (RFP)‐LC3 puncta. Cisplatin induced complete autophagic flux, which was detected via monitoring of p62 degradation and RFP‐GFP‐LC3 expression. Inhibition of autophagy by chloroquine, 3‐methyladenine, or Atg5 knockdown significantly attenuated cisplatin‐induced HBV replication. Additionally, cisplatin‐induced autophagy could be significantly attenuated by using the ROS scavenger N‐acetyl‐l‐cysteine. Mechanically, cisplatin promoted HBV replication and autophagy through ROS/JNK and AKT/mTOR signaling. Inhibition of JNK or activation of Akt/mTOR signaling reversed cisplatin‐mediated autophagy and HBV replication promotion. In contrast, suppression of Akt/mTOR signaling further promoted cisplatin‐induced HBV replication. Finally, pharmacotherapeutic inhibition of autophagy or ROS production impaired HBV production induced by cisplatin in vivo. Together, our results indicate that ROS/JNK and mTOR/AKT‐mediated autophagy plays an important role in cisplatin‐induced HBV reactivation. Graphical abstract Figure. No Caption available. HighlightsCisplatin stimulates HBV replication in vitro and in vivo.Cisplatin induces autophagy to enhance hepatitis B virus replication.Inhibition of autophagy or ROS/JNK axis rendered cisplatin‐induced HBV biosynthesis.Cisplatin promotes HBV replication and autophagy by ROS/JNK and AKT/mTOR pathway.