Endogenous antioxidant response pathways (Nrf2-ARE pathway)

The endogenous antioxidant response pathways, primarily centered on the Nrf2-ARE (Nuclear factor erythroid 2-related factor 2 - Antioxidant Response Element) signaling system, constitute the primary cellular defense mechanism against oxidative and electrophilic stress [1.2.1, 1.3.1]. Under homeostatic conditions, the transcription factor Nrf2 is sequestered in the cytoplasm by Keap1 and targeted for proteasomal degradation [1.2.1, 1.4.3]. Upon exposure to stressors or pharmacological activators, Nrf2 translocates to the nucleus, where it binds to ARE sequences in the promoter regions of over 200 cytoprotective genes, including those for heme oxygenase-1 (HO-1) and glutathione synthesis enzymes [1.3.1, 1.4.1]. This pathway is a major therapeutic target for chronic inflammatory and neurodegenerative diseases, where enhancing antioxidant capacity can mitigate tissue damage [1.2.1, 1.3.3]. However, its role in cancer is complex; while it prevents carcinogenesis in healthy cells, its hyperactivation in established tumors can promote chemoresistance and survival [1.2.4, 1.2.5]. Drugs like dimethyl fumarate and omaveloxolone have been approved for multiple sclerosis and Friedreich's ataxia, respectively, by modulating this pathway [1.4.1, 1.4.3].

Other names

Nrf2-ARE signaling pathwayKeap1-Nrf2-ARE pathwayAntioxidant response element pathwayPhase II antioxidant responseElectrophile response element (EpRE) pathway

Activation of the Nrf2-ARE pathway, typically through the inhibition of Keap1-mediated ubiquitination and degradation of Nrf2, allowing Nrf2 to translocate to the nucleus and induce the transcription of cytoprotective and antioxidant genes [1.2.1, 1.4.3].