Kelch-like ECH-associated protein 1 - Nuclear factor erythroid 2-related factor 2 pathway (KEAP1-NRF2 pathway)

The Kelch-like ECH-associated protein 1 (KEAP1) - Nuclear factor erythroid 2-related factor 2 (NRF2) pathway is the primary cellular defense mechanism against oxidative and electrophilic stress. Under basal conditions, the KEAP1 homodimer acts as a substrate adapter for the CUL3-RING E3 ubiquitin ligase complex, continuously targeting NRF2 for ubiquitination and proteasomal degradation. Upon exposure to stressors or pharmacological activators, sensor cysteine residues on KEAP1 are modified, leading to a conformational change that prevents NRF2 ubiquitination. This allows NRF2 to accumulate and translocate into the nucleus, where it heterodimerizes with small MAF proteins and binds to Antioxidant Response Elements (ARE) to induce the transcription of over 200 cytoprotective genes. These genes encode proteins involved in antioxidant defense, detoxification, and glutathione synthesis. While pharmacological activation of NRF2 is therapeutic in chronic inflammatory, autoimmune, and neurodegenerative diseases, its constitutive activation in many cancers promotes tumor survival, progression, and chemoresistance.

Other names

Keap1-Nrf2-ARE pathwayNFE2L2-KEAP1 pathwayNrf2 signaling pathwayKeap1-Nrf2 systemNRF2/KEAP1 signaling

Activation of the NRF2-mediated antioxidant response by inhibiting the KEAP1-NRF2 protein-protein interaction (PPI) or covalently modifying KEAP1 cysteine residues (e.g., Cys151) to stabilize NRF2 and promote its nuclear translocation.