Figure 5.

The ARE-NRF2-KEAP1 signaling pathway. Several factors (phase II inducers) can activate the ARE-NRF2-KEAP1 pathway to trigger antioxidant enzymes expression (phase II gene products). The pathway starts with the signaling from phase II inducers, such as pharmaceuticals, oxidants, antioxidants, electrophile compounds, dietary compounds, and intracellular signals which can be sensed by cysteine residues on the KEAP1 polypeptide, which release NRF2 to be translocated to the nucleus and bind to the ARE sequences in the gene promoter of antioxidant enzyme encoding genes to start the transcriptional activation of those genes and mount a cellular antioxidant defense response. Mitochondrial ROS/RSN or hydrogen peroxide can also signal on KEAP1 to release NRF2 and start the cellular antioxidant defense.