Nrf2 Antioxidant Response Pathway

Nuclear factor erythroid 2-related factor 2 controls the expression of >200 cytoprotective genes. The master regulator of the cellular antioxidant defense system.

Overview

Under basal conditions, Nrf2 is bound by Keap1 in the cytoplasm and targeted for proteasomal degradation (half-life ~20 minutes). Oxidative stress or electrophilic compounds modify Keap1 cysteine residues, disrupting Nrf2 ubiquitination. Stabilized Nrf2 translocates to the nucleus, dimerizes with Maf proteins, and binds Antioxidant Response Elements (AREs) in promoters of phase II detoxification enzymes (NQO1, HO-1, GSTs, GCL).

Key Steps

1. Basal: Keap1 homodimer binds Nrf2 DLG and ETGE motifs, presenting it to Cul3-E3 ligase for ubiquitination
2. Stress: Electrophiles modify Keap1 Cys151, Cys273, Cys288 → conformational change
3. Nrf2 escapes degradation, accumulates, and translocates to nucleus
4. Nrf2-Maf heterodimer binds ARE (5'-TGACXXXGC-3') in target gene promoters
5. Transcription of phase II enzymes: NQO1, HO-1, GCLC, GCLM, GSTs, SODs
6. Negative feedback: Keap1 is transcriptionally induced by Nrf2, restoring basal suppression

Disease Relevance

• Cancer: Dual role: Nrf2 activation protects normal cells from carcinogenesis (tumor prevention), but constitutive Nrf2 in established tumors promotes chemoresistance. KEAP1 loss-of-function mutations are common in lung cancer.
• Parkinson's: Nrf2 activation protects dopaminergic neurons from oxidative damage. Sulforaphane-mediated Nrf2 induction shows neuroprotective effects in PD models.
• ALS: Nrf2 expression is reduced in ALS motor neurons. Nrf2 activation in astrocytes provides non-cell-autonomous neuroprotection to motor neurons.

Therapeutic Targets

• Sulforaphane: Most potent natural Nrf2 inducer — modifies Keap1 Cys151
• Curcumin: Electrophilic Michael acceptor that modifies Keap1 cysteines
• EGCG: Nrf2 activation via PI3K/Akt-mediated Keap1 phosphorylation
• Methylene Blue: Activates Nrf2 via mild oxidative hormesis