Nrf2 / Keap1 antioxidant response

Category: signaling

Overview

Nrf2 (NFE2L2) is the master transcription factor for antioxidant + phase II detoxification genes. Under basal conditions, Keap1 (cytoplasmic) ubiquitinates Nrf2 → proteasomal degradation. Electrophilic / oxidative stress modifies cysteine residues on Keap1 → Nrf2 released → nuclear translocation → ARE (antioxidant response element) binding → induces HO-1, NQO1, glutathione synthesis, GST, UGT1A enzymes. Many polyphenol + flavonoid + isothiocyanate compounds activate this pathway: sulforaphane (broccoli isothiocyanate — most potent Nrf2 inducer in nature), curcumin, resveratrol, EGCG, quercetin, urolithin-A. Polyphenols are not single-target — they hit Nrf2 + sirtuins + AMPK + cyclic-AMP downstream of metabolite-based signaling. Long-term clinical trials are mostly null for hard outcomes despite robust mechanistic signals — the bioavailability + first-pass conjugation gap remains poorly bridged.

Organ Systems

• immune-hematologic
• digestive

Pathway Steps

1. oxidative-or-electrophilic-stress → keap1-cysteine-modification — via electrophile/ROS oxidizes Keap1 Cys151/Cys273/Cys288 → conformational change → Nrf2 release. Under basal conditions KEAP1 constantly targets the transcription factor NRF2 for degradation. Oxidative or electrophilic stress modifies reactive cysteines on KEAP1, disabling it — so KEAP1 is a thiol-based sensor that detects “electrophilic load”, the trigger of the antioxidant response.
2. nrf2-stabilization → antioxidant-gene-transcription — via nuclear translocation → ARE binding → HO-1/NQO1/GST/UGT/GCL transcription. With KEAP1 disabled, NRF2 is stabilized, accumulates, and enters the nucleus to drive antioxidant-response-element (ARE) genes — glutathione synthesis, NQO1, HO-1, and phase-II detox enzymes. This master cytoprotective program is activated by dietary electrophiles (sulforaphane) and the drug dimethyl fumarate.

Known Modulators

• sulforaphane (activator) — Keap1 (cysteine modification → Nrf2 release). isothiocyanate from broccoli/sprouts; most potent natural Nrf2 inducer; phase 2 trial in autism (Singh 2014)
• curcumin (activator) — Nrf2 + NF-κB + COX-2 (multi-target). turmeric; poor bioavailability (low water solubility) — phytosomal/Meriva/piperine formulations 3-29× better
• curcumin meriva (activator) — Nrf2 (phospholipid-complex formulation). phytosomal curcumin; ~29× bioavailability of plain curcumin (Cuomo 2011)
• resveratrol (activator) — SIRT1 + Nrf2 + AMPK. stilbenoid from red grape skins; sirtuin activation drives healthspan claims; clinical results mixed for cardiovascular outcomes
• pterostilbene (activator) — Nrf2 + SIRT1 (dimethyl-resveratrol). resveratrol analog; better oral bioavailability than parent; similar mechanistic profile
• egcg (activator) — Nrf2 + COMT inhibition + receptor cross-talk. epigallocatechin-3-gallate; green tea catechin; hepatotoxicity at high doses (>700 mg/d EGCG)
• quercetin (activator) — Nrf2 + COMT + xanthine oxidase + mast cell stabilization. broad-spectrum flavonoid; poor bioavailability; isoquercetin formulations ~20× better
• urolithin a (activator) — mitophagy + Nrf2. gut microbiota metabolite of ellagitannins; mitochondrial biogenesis; supplement form (Mitopure) bypasses microbiome variability
• urolithin b (activator) — mitophagy + Nrf2. related urolithin; less commercialized than urolithin-A; same gut-metabolite source
• ergothioneine (activator) — mitochondrial antioxidant (OCTN1 transporter-mediated uptake). unique amino-acid antioxidant; OCTN1-concentrated in tissues; mushroom-rich diets
• fisetin (activator) — senolytic + Nrf2. flavonoid; senescent-cell-eliminating activity in animal models; strawberry-rich source
• hesperidin (activator) — Nrf2 + COMT modulation. citrus flavanone; antioxidant + venotonic; OTC for chronic venous insufficiency in Europe
• kaempferol (activator) — Nrf2 + estrogen-receptor modulation. plant-derived flavonoid; broad antioxidant + estrogen-like activity
• apigenin (activator) — Nrf2 + CYP inhibition + benzodiazepine-site BZD. flavonoid; chamomile component; weak BZD-site activity → sedation; CYP1A2/2C9 inhibitor
• luteolin (activator) — Nrf2 + mast cell stabilizer. flavonoid; allergy/mast-cell claims; quercetin-class
• catechin (activator) — Nrf2 + COMT. tea/cocoa flavanol; lesser potency than EGCG; antioxidant + vasodilator claims
• epicatechin (activator) — Nrf2 + nitric oxide release. cocoa flavanol; vasodilation + endothelial function studied
• naringenin (activator) — Nrf2 + CYP3A4 modulator (grapefruit constituent — but naringin is the bigger DDI driver). citrus flavanone; OATP inhibition for fexofenadine; mild CYP modulation
• rutin (activator) — Nrf2 + venous tone. flavonoid glycoside; chronic venous insufficiency; supplement claim
• silymarin (activator) — Nrf2 + hepatoprotection. milk thistle flavonolignan; silibinin is the major active; hepatoprotective claims + Amanita mushroom poisoning antidote (silibinin IV)
• baicalein (activator) — Nrf2 + COX-2 + lipoxygenase. Scutellaria flavone; anti-inflammatory + neuroprotective claims
• ellagic acid (activator) — Nrf2 + carcinogen metabolism modulation. pomegranate / berry polyphenol; ellagitannin parent; precursor to urolithin-A microbiome metabolite
• chlorogenic acid (activator) — AMPK + Nrf2. coffee polyphenol; glucose homeostasis + antioxidant
• caffeic acid (activator) — Nrf2 + COX-2. phenylpropanoid; widespread in plants; antioxidant building block
• ferulic acid (activator) — Nrf2. phenylpropanoid; rice bran + whole grains; UV photoprotection topical
• rosmarinic acid (activator) — Nrf2 + COX-2. rosemary/lemon balm polyphenol
• hydroxytyrosol (activator) — Nrf2 + LDL protection. olive-oil phenol; cardiovascular Mediterranean-diet active
• oleocanthal (activator) — COX inhibitor (ibuprofen-like) + Nrf2. EVOO phenol; chemically related to ibuprofen pharmacology + Mediterranean cardiovascular
• oleuropein (activator) — Nrf2 + ACE inhibitor. olive-leaf glycoside; BP + glucose claims
• sesamin (activator) — tocopherol-sparing + lipid. sesame lignan; raises serum γ-tocopherol via metabolic block; lipid claim
• grape seed extract (activator) — OPC (oligomeric proanthocyanidins) antioxidant. OPCs; cardiovascular + skin claims; bioavailability limited
• theaflavin (activator) — Nrf2 + cholesterol modulation. black-tea fermentation phenol; lipid claims
• cyanidin (activator) — Nrf2 + anthocyanin antioxidant. red/purple anthocyanin; berry + grape skin
• daidzein (activator) — estrogen-receptor partial agonist (isoflavone). soy isoflavone; ER-β preferential; menopausal symptom claim
• delphinidin (activator) — Nrf2 + anthocyanin. blue/purple anthocyanin
• genistein (activator) — estrogen-receptor partial agonist (isoflavone). soy isoflavone; tyrosine kinase inhibitor activity at high doses
• procyanidin b2 (activator) — Nrf2. cacao/apple OPC; antioxidant
• icariin (activator) — PDE5 inhibitor + bone (Epimedium). horny goat weed flavonoid; PDE5 inhibition + bone-density claims
• milk thistle silibinin (activator) — hepatoprotection (purified silibinin). purified silibinin; Amanita poisoning IV antidote
• taxifolin (activator) — Nrf2 + antioxidant. dihydroquercetin; pine-bark extract
• limonene (activator) — antioxidant + chemopreventive. citrus terpene; chemoprevention research
• linalool (activator) — NMDA/GABA modulation. lavender terpene; anxiolytic claim
• myrcene (activator) — GABA-A + sedative claim. cannabis + hops terpene
• alpha pinene (activator) — AChE inhibitor + bronchodilator. pine terpene
• beta pinene (activator) — AChE inhibitor + antimicrobial. pine terpene
• geraniol (activator) — antimicrobial + insect repellent. rose/geranium terpene
• bisabolol (activator) — anti-inflammatory + antimicrobial. chamomile sesquiterpene
• cinnamaldehyde (activator) — TRPA1 + Nrf2 + insulin sensitivity. cinnamon active; cross-link: trp_channel_sensory_transduction

References

• PMID 29717933
• PMID 30610225
• PMID 24647116