Nuclear factor erythroid 2-related factor 2 (NFE2L2) signaling pathway (Nrf2-ARE pathway)

The Nuclear factor erythroid 2-related factor 2 (Nrf2)-Antioxidant Response Element (ARE) pathway is a master regulatory system essential for cellular redox homeostasis and cytoprotection. Under normal physiological conditions, Nrf2 is primarily sequestered in the cytoplasm by Kelch-like ECH-associated protein 1 (Keap1), which facilitates its continuous ubiquitination and proteasomal degradation. Upon exposure to oxidative stress or electrophilic chemical stimuli, critical cysteine residues on Keap1 are modified, leading to the stabilization and nuclear translocation of Nrf2. Once in the nucleus, Nrf2 binds to ARE sequences to coordinate the transcription of a vast battery of antioxidant, detoxifying, and anti-inflammatory genes, such as HO-1 and NQO1. Clinically, this pathway is targeted by activators like Dimethyl fumarate and Omaveloxolone for the treatment of Multiple Sclerosis and Friedreich's Ataxia, respectively. However, the pathway exhibits a complex 'dual role' in oncology: while it prevents cancer initiation in healthy tissues, its aberrant constitutive activation in established cancer cells can drive tumor progression, metabolic reprogramming, and resistance to therapy.

Other names

NFE2L2 signaling pathwayNrf2-Keap1-ARE pathwayAntioxidant response element pathwayNuclear factor erythroid-derived 2-like 2 pathway

Activation typically occurs via the disruption of the Keap1-Nrf2 interaction, preventing Keap1-mediated ubiquitination and proteasomal degradation of Nrf2. This leads to the stabilization and nuclear translocation of Nrf2, where it heterodimerizes with small MAF proteins and binds to the Antioxidant Response Element (ARE) in the promoter regions of cytoprotective genes to induce their transcription. Inhibitors (e.g., in cancer) may target the Nrf2 DNA-binding domain or disrupt its transcriptional activity.