Nuclear factor erythroid 2-related factor 2 (Nrf2)

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master transcriptional regulator of the antioxidant and cytoprotective response. Under basal conditions, Nrf2 is sequestered in the cytoplasm by Keap1 and targeted for proteasomal degradation; however, upon exposure to oxidative stress or electrophiles, Nrf2 translocates to the nucleus and binds to the Antioxidant Response Element (ARE) to initiate the transcription of genes involved in detoxification and glutathione synthesis (PMID: 28735877, UniProt: Q16236). This pathway is a critical therapeutic target for diseases characterized by oxidative stress and inflammation, such as multiple sclerosis and Friedreich's ataxia (PMID: 32103363). While Nrf2 activation is generally protective in healthy tissues, its constitutive activation in certain cancers can promote tumor survival and drug resistance, presenting a complex challenge for drug development (PMID: 23434760). Current pharmacological strategies primarily focus on Nrf2 activators like dimethyl fumarate and omaveloxolone, which disrupt the Keap1-mediated inhibition of Nrf2 to enhance cellular defense mechanisms (StatPearls: NBK549780).

Other names

NFE2L2Nuclear factor erythroid-derived 2-like 2HEBP1Nrf2-ARE pathway

Nrf2 activators typically work by inhibiting the Keap1-Nrf2 interaction or modifying Keap1 cysteine residues, preventing Nrf2 ubiquitination and degradation. This allows Nrf2 to translocate to the nucleus, heterodimerize with small Maf proteins, and bind to the Antioxidant Response Element (ARE) in the promoter regions of cytoprotective genes.