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

The Nuclear factor erythroid 2-related factor 2–Kelch-like ECH-associated protein 1 (NFE2L2–KEAP1) pathway serves as the primary cellular defense mechanism against oxidative and electrophilic stress (UniProt Q16236). Under basal conditions, KEAP1 acts as a substrate adapter for the Cullin 3-based E3 ubiquitin ligase, targeting NFE2L2 for constant proteasomal degradation (UniProt Q14145). When cells encounter stressors, specific cysteine residues on KEAP1 are modified, leading to the stabilization and nuclear translocation of NFE2L2, which then activates the transcription of a battery of cytoprotective genes (PubMed: 25970055). This pathway is a major therapeutic target for chronic inflammatory and neurodegenerative diseases, with drugs like dimethyl fumarate and omaveloxolone already approved for clinical use (FDA, 2023). However, the pathway exhibits a dual role in pathology; while it prevents cancer initiation in healthy tissues, its hyperactivation in established tumors can promote chemoresistance and metabolic reprogramming (PubMed: 23435224). Consequently, drug development focuses on both NFE2L2 activators for cytoprotection and NFE2L2 inhibitors for oncology applications.

Other names

NRF2-KEAP1 signaling pathwayNFE2L2-KEAP1 axisAntioxidant response element (ARE) pathwayNRF2 pathwayNFE2L2–KEAP1 antioxidant pathway

NRF2 activators typically function by covalently modifying cysteine sensors on KEAP1 or by sterically hindering the KEAP1-NRF2 protein-protein interaction, which prevents NRF2 ubiquitination and allows it to accumulate and activate cytoprotective gene expression via Antioxidant Response Elements (ARE) (PubMed: 25970055).