Kelch-like ECH-associated protein 1–nuclear factor erythroid 2-related factor 2–antioxidant response element signaling pathway (Keap1–Nrf2–ARE pathway)

The Keap1-Nrf2-ARE pathway is a central redox-sensitive cell signaling axis that monitors and manages cellular response to oxidative and electrophilic stress. Under basal conditions, Keap1 binds Nrf2 in the cytoplasm, promoting its ubiquitination and degradation via the proteasome. Upon exposure to oxidative or electrophilic agents, cysteine residues in Keap1 become modified, leading to release and stabilization of Nrf2. Stabilized Nrf2 translocates to the nucleus, dimerizes with small Maf proteins, and binds to antioxidant response elements (ARE) in the promoter regions of target genes, driving the expression of cytoprotective and detoxification enzymes. This pathway is vital for cell survival and homeostatic maintenance, but can also confer a growth advantage to malignant cells and enhance chemoresistance when aberrantly activated.

Other names

Keap1-Nrf2 pathwayNrf2/Keap1 signalingNRF2 pathwayAntioxidant response element pathway

Covalent modification or alkylation of Keap1 cysteine residues, leading to release/activation of Nrf2. Inhibition of Nrf2 degradation through Keap1/CUL3 ubiquitin ligase complex inhibition. Stabilization/activation of Nrf2, allowing nuclear translocation and ARE-driven gene transcription.