Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway (Nrf2/HO-1 pathway)

The Keap1/Nrf2/HO-1 signaling pathway is the primary cellular defense mechanism against oxidative and electrophilic stress [PubMed: 25991492]. Under basal conditions, the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) is sequestered in the cytoplasm by Kelch-like ECH-associated protein 1 (Keap1), which targets it for ubiquitination and proteasomal degradation [UniProt: Q16236, Q14145]. Upon exposure to oxidative stress or specific therapeutic agents, Keap1 is inactivated, allowing Nrf2 to translocate to the nucleus and bind to Antioxidant Response Elements (ARE) [PubMed: 32103301]. This binding induces the expression of various cytoprotective genes, most notably Heme oxygenase 1 (HO-1), which exerts potent antioxidant and anti-inflammatory effects [UniProt: P09601]. Drugs such as dimethyl fumarate and omaveloxolone target this pathway to treat conditions like multiple sclerosis and Friedreich's ataxia [FDA: Skyclarys, Tecfidera]. However, chronic Nrf2 activation can also promote the survival and chemoresistance of cancer cells, presenting a significant challenge in oncology [PubMed: 29453248]. Therapeutic strategies often focus on the covalent modification of Keap1 to stabilize Nrf2 and enhance the cellular antioxidant capacity. Monitoring biomarkers like HO-1 and NQO1 is essential for assessing the efficacy of these treatments in clinical settings.

Other names

Keap1-Nrf2-ARE pathwayNFE2L2-HMOX1 axisAntioxidant response element pathwayNrf2 signaling pathwayKeap1/Nrf2/HO-1 axis

Pharmacological activation of the pathway typically involves the covalent modification of Keap1 cysteine residues, which disrupts the Keap1-Nrf2 interaction and prevents Nrf2 degradation, leading to the induction of cytoprotective genes like HO-1 [PubMed: 32103301].