Fig. 1: Chronic viral infections mediated abnormal proliferation and apoptosis of hepatocytes by interfering with MDM2–p53 axis.

After HBV enters into the cytoplasm via NTCP, the cccDNA of HBV can integrate into host chromosomes, which provoked DNA damage of the host and p53 activation. Normally, two types of pathways can be activated, both of which are related with cell survival inhibitor: p53–Bax–mitochondria-induced apoptosis, and p53/fas-mediated cell death. However, HBx can directly bind to p53 that inhibit the infected hepatocyte apoptosis from p53–Bax–mitochondria. Moreover, HBx can disturb the transcriptional activity of p53 by binding with MDM2, which might impair p53-mediated DNA repairing. In addition, HBx binding to MDM2 can upregulate the expression of COX2 that can promote TGF-β1 expression from HSC, and thereby block hepatocyte apoptosis. Likewise, HBeAg can inhibit the p53/Fas pathway-mediated cell death. In addition, HBV can induce a small nucleolar RNA expression (SNORA18L5) in hepatocytes, which can mediate p53 ubiquitination and degradation by preventing RPL5 and RPL11 escape into the nucleoplasm to bind MDM2. Unlike HBV, the replication of HCV is mainly processed around the ER, which can induce chronic ER stress, oxidative stress, and Nrf2 activation. Nrf2 can induce MDM2-mediated Rb and p53 proteosomal degradation that might block the Rb/E2F pathway-mediated inhibitor of cell-cycle progression of infected hepatocytes. Moreover, ER stress can further promote the cell cycle by increasing MDM2 expression. Likewise, HCV can directly inhibit the expression of KLF6 that can contribute to cell-cycle arrest by promoting p53-induced MDM2 degradation. In addition, HCV can overcome the ROS/p53-mediated apoptosis by promoting MDM2 accumulation and inducing ub-mediated proteasomal degradation of p53. Interestingly, HCV can induce naive CD4⁺T-cell exhaustion via p53-dependent manner, which can avoid infected hepatocytes to be killed by T cells.