Nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1-Antioxidant Response Element pathway (Nrf2-Keap1-ARE pathway)

The Nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1)-Antioxidant Response Element (ARE) pathway is the master regulator of the cellular antioxidant response and xenobiotic metabolism [1]. Under homeostatic conditions, Keap1 functions as a substrate adapter for the Cullin 3-based E3 ubiquitin ligase complex, which continuously targets Nrf2 for ubiquitination and subsequent proteasomal degradation [2]. When cells encounter oxidative stress or electrophiles, Keap1 is inactivated through the modification of its reactive cysteine residues, allowing Nrf2 to stabilize, accumulate, and translocate into the nucleus [3]. In the nucleus, Nrf2 heterodimerizes with small Maf proteins and binds to the ARE sequences in the promoter regions of over 200 cytoprotective genes, including heme oxygenase-1 (HMOX1) and NAD(P)H quinone dehydrogenase 1 (NQO1) [1,4]. Pharmacological activation of this pathway is a proven therapeutic strategy for neurodegenerative and inflammatory conditions, as evidenced by the approval of dimethyl fumarate for multiple sclerosis and omaveloxolone for Friedreich's ataxia [5,6]. However, the pathway exhibits a dual role in oncology; while it prevents initial carcinogenesis, its constitutive activation in established tumors promotes survival, metabolic reprogramming, and resistance to chemotherapy [7].

Other names

Nrf2 signaling pathwayKeap1-Nrf2 pathwayNFE2L2-KEAP1-ARE axisAntioxidant response element pathway

Activation of Nrf2 by inhibiting Keap1-mediated degradation, leading to nuclear translocation and transcription of antioxidant response element (ARE)-driven genes.