Nuclear factor erythroid 2-related factor 2–Heme oxygenase antioxidant response pathway (Nrf2–HO pathway)

The Nuclear factor erythroid 2-related factor 2 (Nrf2)–Heme oxygenase (HO) pathway is a master regulatory system for the cellular antioxidant response. Nrf2 is a transcription factor that, upon activation by oxidative stress or pharmacological agents, translocates to the nucleus to induce the expression of Heme oxygenase-1 (HO-1), an enzyme that degrades heme into cytoprotective byproducts like biliverdin and carbon monoxide (PMID: 24011514). This pathway plays a critical role in protecting tissues from inflammatory damage and oxidative injury, making it a key therapeutic target in conditions like multiple sclerosis and Friedreich's ataxia (PMID: 31010466). Drugs such as dimethyl fumarate and omaveloxolone function by activating this pathway to enhance cellular resilience. However, the pathway is also implicated in cancer progression, where its overactivation can protect malignant cells from chemotherapy and apoptosis, a phenomenon known as the “Nrf2 paradox” (PMID: 29298424). Consequently, while activation is beneficial in degenerative diseases, inhibition may be required in certain oncological contexts. The pathway also involves Heme oxygenase-2 (HO-2), a constitutively expressed isoform that provides basal protection in the central nervous system and vasculature.

Other names

Nrf2-ARE pathwayNFE2L2-HMOX1 axisAntioxidant response element signalingKeap1-Nrf2-HO-1 pathway

Activation of the Nrf2 transcription factor, typically through the modification of Keap1 cysteine residues, which prevents Nrf2 degradation and allows its nuclear translocation to induce the transcription of Heme oxygenase-1 (HO-1) and other antioxidant genes.