Schematic diagram of the different consequences of genetic loss or mutation of KEAP1 and pharmacological inhibition of KEAP1 by RTA 405.

<p><b><i>Upper panel</i></b>. Under normal physiological conditions, KEAP1 promotes the degradation of its target proteins: NRF2, BCL2, and IKKβ. NRF2 target antioxidant genes and NF-κB target cell survival genes are not expressed. <b><i>Middle panel</i></b>. When KEAP1 is mutated or KEAP1 levels are reduced, it is no longer able to promote degradation of its target proteins. Therefore NRF2, IKKβ, and BCL2 levels are elevated. As a result, NRF2 accumulates, translocates to the nucleus and increases expression of antioxidant genes. IKKβ levels also accumulate and phosphorylate IκBα, resulting in its degradation. When IκBα is degraded, NF-κB is able to translocate to the nucleus and increase expression of cell survival genes. Elevated BCL2 levels inhibit apoptosis. <b><i>Lower panel</i></b>. RTA 405 binds to KEAP1 and blocks its ability to promote NRF2 degradation. NRF2 then translocates to the nucleus where it is transcriptionally active. However, RTA 405 does not inhibit the ability of KEAP1 to promote BCL2 or IKKβ degradation; therefore, the levels of these proteins are not elevated. Furthermore, RTA 405 also directly inhibits the activity of IKKβ, further reducing downstream NF-κB activity and inhibiting NF-κB target gene expression. RTA 405 also increases apoptosis independently of KEAP1/NRF2.