Nuclear factor erythroid 2-related factor 2 (Nrf2)–Heme oxygenase-1 (HO-1) signaling pathway (Nrf2–HO-1 pathway)

The Nuclear factor erythroid 2-related factor 2 (Nrf2)–Heme oxygenase-1 (HO-1) signaling pathway is a master regulator of the cellular antioxidant response (Loboda et al., 2016, "Heme Oxygenase-1 and the Role of Its Metabolites in Inflammation and Oxidative Stress"). Under basal conditions, Nrf2 is kept at low levels by Keap1-mediated ubiquitination; however, oxidative stress triggers its stabilization and nuclear translocation (He et al., 2020, "The Keap1-Nrf2 pathway: promising therapeutic target for chronic diseases"). Once in the nucleus, Nrf2 binds to Antioxidant Response Elements (ARE) to drive the expression of HO-1, which degrades heme into cytoprotective metabolites like biliverdin and carbon monoxide (PubMed: 27036913). This pathway is targeted by drugs like dimethyl fumarate for multiple sclerosis and omaveloxolone for Friedreich's ataxia to mitigate oxidative damage (FDA, 2023). While beneficial in chronic inflammatory diseases, its overactivation in cancer cells can promote tumor survival and drug resistance, a phenomenon known as the "Nrf2 paradox" (Sporn & Liby, 2012, "NRF2 and cancer: the good, the bad and the importance of context").

Other names

NFE2L2–HMOX1 axisNrf2/ARE signaling pathwayKeap1-Nrf2-ARE pathwayAntioxidant response element (ARE) pathway

Activation of the Nrf2 transcription factor, typically through the inhibition of its negative regulator Keap1, leading to the transcriptional upregulation of Heme oxygenase-1 (HO-1) and other antioxidant response element (ARE)-containing genes (He et al., 2020).