The Nrf2-Keap1-HO-1 pathway. The transcription factor, Nrf2, is sequestered in the cytoplasm by the cysteine- (Cis-) rich Kelch-like ECH-associated protein 1 (Keap1). The binding of Nrf2 with Keap1 is also the basis for its degradation through the ubiquitin- (Ub-) based proteosomal pathway. Under OS or induction by ROS and drugs, the Keap1 response through Cis could lead to the release and stabilization of Nrf2 [27
]. The phosphorylation of Nrf2 also leads to its release and translocation into the nucleus. Nrf2 as a conjugate with the Maf proteins binds to the antioxidant response element (ARE) to induce the transcription of target genes including HO-1. The degradation of heme to an antioxidant bilirubin via the biliverdin intermediate is also shown. Other products of the system induce carbon monoxide (CO) and Fe2+
which further induce ferritin production.