Nuclear factor erythroid 2-related factor 2–Keap1–heme oxygenase-1 pathway (Nrf2–Keap1–HO-1 pathway)

The Nuclear factor erythroid 2-related factor 2–Keap1–heme oxygenase-1 pathway is a central cellular signaling cascade regulating redox homeostasis, cytoprotection, and the response to oxidative and electrophilic stress. In this pathway, Keap1 (Kelch-like ECH-associated protein 1) acts as the negative regulator of Nrf2, targeting it for ubiquitin-mediated proteasomal degradation under homeostatic conditions. Upon oxidative stress or exposure to electrophilic agents, key cysteine residues in Keap1 are modified, causing the release and stabilization of Nrf2, which translocates into the nucleus, heterodimerizes with small Maf proteins, and binds to antioxidant response elements (ARE) in the promoters of many cytoprotective genes, including heme oxygenase-1. Nrf2 activation upregulates a broad gene battery involved in antioxidant defense, detoxification, and inflammation modulation. Pharmacological targeting of this pathway is under intense research for diseases linked to oxidative damage, but persistent activation may also contribute to tumorigenesis, chemoresistance, and altered immune responses[1][2][3][4][5][6][7].

Other names

Nrf2–Keap1 pathwayKeap1–Nrf2–HO-1 pathwayKeap1–Nrf2/ARE pathwayNuclear factor erythroid 2–related factor 2 (Nrf2) signaling axisKelch-like ECH-associated protein 1–Nrf2 pathway

Activation by electrophilic/oxidative stressors triggers Nrf2 release from Keap1, nuclear translocation, and transcriptional activation of cytoprotective genes; Pharmacological activators modify Keap1 cysteine residues, inhibit ubiquitination of Nrf2, and stabilize Nrf2 protein, leading to increased expression of antioxidant/detoxifying genes; Inhibitors may stabilize Keap1-mediated degradation of Nrf2, blocking protective gene upregulation