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

The Kelch-like ECH-associated protein 1–nuclear factor erythroid 2-related factor 2 signaling pathway is a central cellular defense mechanism against oxidative and electrophilic stress. Under basal conditions, Keap1 binds to Nrf2 in the cytoplasm, promoting its ubiquitination and proteasomal degradation. Upon exposure to reactive oxygen species or electrophiles, modifications on cysteine residues within Keap1 disrupt this interaction, allowing stabilized Nrf2 to translocate into the nucleus. There it dimerizes with small Maf proteins and binds antioxidant response elements (ARE) in DNA promoters to induce transcription of detoxifying enzymes and antioxidants. This adaptive response protects cells from damage but can be hijacked by cancers for growth advantage. The dual role makes this axis both a promising therapeutic target for diseases involving oxidative damage—such as neurodegeneration, inflammation, diabetes—and a potential contributor to therapy resistance when overactivated in malignancy. Drugs that modulate this interaction are under investigation; some have reached clinical use while others were discontinued due to adverse effects.

Other names

Keap1/Nrf2/ARE pathwayNrf2/Keap1 signalingKelch-like ECH-associated protein 1–NF-E2-related factor 2 pathwayKeap1-Nrf2 system

Activation or inhibition of Nrf2 nuclear translocation by modulating the interaction between Keap1 and Nrf2, leading to upregulation or downregulation of antioxidant response element (ARE)-driven gene expression. Activators disrupt Keap1-mediated ubiquitination/degradation of Nrf2. Inhibitors may block excessive Nrf2 activity in cancer.