Nuclear factor erythroid 2-related factor 2 (NFE2L2) (Nrf2)

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a basic leucine zipper (bZIP) transcription factor that serves as the master regulator of the cellular antioxidant and detoxification response. Under homeostatic conditions, Nrf2 is kept at low levels through sequestration in the cytoplasm by its inhibitor, Kelch-like ECH-associated protein 1 (Keap1), which facilitates its ubiquitination and degradation. Upon exposure to oxidative or electrophilic stress, the Keap1-Nrf2 interaction is disrupted, allowing Nrf2 to accumulate, translocate to the nucleus, and induce the expression of a broad battery of cytoprotective genes involved in redox balance and anti-inflammatory pathways. In therapeutic contexts, Nrf2 activators like Dimethyl fumarate and Omaveloxolone are utilized to treat neurodegenerative and autoimmune conditions by boosting endogenous defenses. However, the pathway presents a 'double-edged sword' in oncology, as constitutive Nrf2 activation can provide cancer cells with a survival advantage, leading to enhanced proliferation and resistance to radiation and chemotherapy. Strategic modulation of Nrf2 signaling remains a high-priority area in drug development for chronic inflammatory and age-related diseases.

Other names

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

Nrf2 activators typically function by inhibiting the Keap1-mediated ubiquitination and subsequent proteasomal degradation of Nrf2, allowing the protein to accumulate and translocate to the nucleus. Once in the nucleus, Nrf2 heterodimerizes with small Maf proteins and binds to the Antioxidant Response Element (ARE) in the promoter regions of various cytoprotective genes, initiating their transcription.