Schematic depiction of the potential signals induced by pre-S mutants and the candidate targets for chemoprevention. Both types of pre-S mutants can induce endoplasmic reticulum (ER) stress signals, which may lead to oxidative stress and DNA damage, leading to genomic instability. The pre-S mutants may also activate two signal pathways to protect the hepatocytes from apoptosis, one involving nuclear factor (NF)-κB to upregulate cyclooxygenase-2 (COX-2) and the other vascular endothelial growth factor to activate Akt/mammalian target of Rapamy- cin (mTOR) signaling. Pre-S2 mutant can additionally induce an ER stress-independent c-Jun activation domain binding protein 1 (JAB1)/ p27/retinoblastoma (Rb)/adenovirus E2 promoter binding factor/cyclin A signal to initiate cell cycle progression. Combined effects of genomic instability and cell proliferation will potentially result in carcinogenesis. Resveratrol and Silymarin are two nature products could be used to target PPAR-α/γ and mTOR signal cascade for chemoprevention in high risk HBV carriers. Cdk2, cyclin-dependent kinase 2; HBV, hepatitis B virus; ROI, reactive oxygen intermediate.