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

The Nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway is the master regulator of the cellular antioxidant response and redox homeostasis (PMID: 30766188). 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 (UniProt: Q16236). When cells encounter oxidative stress or electrophiles, Keap1 is inactivated through the modification of its sensor cysteine residues, allowing Nrf2 to stabilize, accumulate, and translocate into the nucleus. Once in the nucleus, Nrf2 heterodimerizes with small Maf proteins and binds to the Antioxidant Response Element (ARE) to drive the transcription of a battery of cytoprotective genes, including those for glutathione synthesis and phase II detoxification enzymes (PMID: 28239971). This pathway is a significant therapeutic target in inflammatory, neurodegenerative, and metabolic diseases, with approved drugs like dimethyl fumarate for multiple sclerosis and omaveloxolone for Friedreich's ataxia (FDA). However, the pathway's role is complex, as constitutive Nrf2 activation in certain cancers can promote tumor survival and resistance to chemotherapy, a phenomenon often referred to as the "dark side" of Nrf2 (PMID: 23435224). Pharmacological modulation requires careful balancing to achieve cytoprotection without inadvertently supporting malignancy or causing cardiovascular complications.

Other names

NFE2L2-KEAP1 pathwayAntioxidant Response Element (ARE) pathwayNrf2 signaling pathwayNrf2-ARE pathway

Activation of the Nrf2-mediated antioxidant response by inhibiting Keap1-dependent ubiquitination and degradation of Nrf2, leading to its nuclear translocation and induction of cytoprotective genes (PMID: 32103301).