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

The **Nuclear factor erythroid 2-related factor 2–Kelch-like ECH-associated protein 1 (NRF2–KEAP1) signaling pathway** is a master regulator of cellular defense against oxidative and electrophilic stress[1][2][3][5]. Under basal conditions, KEAP1 targets NRF2 for ubiquitin-mediated proteasomal degradation. Upon exposure to oxidative stress or electrophilic agents, KEAP1 undergoes cysteine modifications, releasing NRF2, which accumulates, translocates to the nucleus, and induces transcription of antioxidant and detoxification genes by binding to the antioxidant response element (ARE)[1][2][3]. This pathway is cytoprotective but can be hijacked by cancer cells to promote proliferation, survival, and drug resistance, making it both a promising therapeutic target and a concern for tumorigenesis[1][4][5]. Pharmaceutical modulation of this pathway is being investigated for cancer, chronic inflammatory conditions, and neurodegenerative diseases[2][5].

Other names

KEAP1–NRF2 pathwayNFE2L2–KEAP1 pathwayNRF2–KEAP1 axisKEAP1–NFE2L2 signalingKEAP1–NRF2–ARE pathway

NRF2 activation by inhibiting KEAP1-mediated degradation (e.g., electrophilic or oxidative modification of KEAP1 cysteines leads to NRF2 stabilization and nuclear accumulation); Direct NRF2 inhibition (rare); Indirect KEAP1 inhibition; Transcriptional upregulation of detoxification and antioxidant genes