Figure 1. Model of TLR4-mediated DNA repair in the regulation of DEN-induced HCC. The genotoxic carcinogen DEN induces DNA damage and liver injury, which causes the accumulation of ROS and DAMPs released from the injured liver tissue. Accumulated ROS sustain DNA damage and genome instability to lead to hepatocyte transformation, whereas DAMPs interaction with TLR4 stimulates an immune response to liver damage and initiates or supports senescence and autophagy, which can remove accumulated ROS, repair DNA damage and decrease SQSTM1 aggregates. In particular, TLR4-mediated immune responses promote the expression of the DNA repair protein XRCC5-XRCC6 when undergoing DEN insult. XRCC6 can initiate a DNA repair response and rescue cellular senescence and autophagy flux, which defends against HCC development and progression. SASPs, senescence-association secreted proteins.