Nrf2 (nuclear factor erythroid 2-related factor 2) is a transcription factor that protects diverse tissues (lung, intestine, neurons, immune cells, and others) from a wide variety of stressors and toxins, including carcinogens, mutagens, electrophiles, starvation, inflammation, UV light and environmental pollutants. This pathway senses chemical and physical stress, rapidly mounting a genomic defense system that enhances tissue resilience, antioxidant defenses and detoxification capacity. Genes induced by Nrf2 include enzymes that synthesize glutathione, antioxidant enzymes, and phase II conjugation enzymes, expediting clearance of reactive oxygen species and xenobiotics. Clinical indications for Nrf2 activation range from environmental exposures to neurodegenerative conditions.
The Nrf2 axis may sound novel, but good activators are strikingly omnipresent in fruits and vegetables. You’re already exposed to hundreds, if not thousands, of potential activators in a plant based diet. Of note, Brassica (cruciferous) vegetables are a very rich source of potent, well-researched activators (isothiocyanates and sulforaphane). Other examples are polyphenols (flavonoids and chalcones from fruits, vegetables and and tea) and stilbenes (resveratrol). Many triterpenoids found in herbs, spices and medicinal plants are also effective activators.
Potent activators represent mild stressors; these include exercise (oxidative stress), caloric restriction (energetic stress), and phytochemicals in the diet (potential toxins). Activation of the pathway enhances autophagy, improves mitochondrial bioenergetics, increases insulin sensitivity and accelerates urinary excretion of benzene and other environmental contaminants.
Effective activators often have redox-active functional groups (e.g. Michael acceptors or phenolic ring systems) that react with cysteine residues on Keap1, a protein that normally restrains Nrf2 in the cytosol under basal conditions (hence, Nrf2 activators are technically Keap1 inhibitors). These properties often predict in vitro success, but they may simultaneously impede oral bioavailability and/or stability. Challenges in clinical development also include unwanted presystemic metabolism and a hormetic, bell-shaped dose-response relationship (meaning that low doses work better than high doses, but we’re not sure where to draw the line).
Nutraceutical forerunners of clinical readiness, with excellent safety profiles, include sulforaphane, resveratrol and curcumin. Comparative studies are still needed to assess their relative efficacy. Whether Nrf2 is really clinical mechanism of action for these compounds remains unclear– they could be working via AMPK/SIRT1, NFkappaB, or other stress-induced pathways that improve metabolic and cellular homeostasis.
Therefore, with supplementation, you might get a good clinical outcome with an ambiguous mechanism of action. Not a bad thing at all!
I once knew a blossoming racecar enthusiast who repaired his Sunbeam with the maxim “do it now, learn how later.”
The punchline: The practical end of Nrf2 is disappointingly redundant with familiar guidelines for healthy living. Exercise regularly, avoid caloric excess, and eat fruits and vegetables. An evidence-based, “cutting-edge” twist: Eat your broccoli (but you’ve heard that before, too).
Further Reading
Houghton CA, et al. Sulforaphane and Other Nutrigenomic Nrf2 Activators: Can the Clinician’s Expectation Be Matched by the Reality? Oxid Med Cell Longev. 2016;2016:7857186.
Heim KC and Spinella MJ. https://experts.illinois.edu/en/publications/natural-products-in-the-prevention-of-cancer-a-review CRC Press. 2015; 361–390 (chapter 21).
Zhou Y, et al. Recent Advances of Natural Polyphenols Activators for Keap1-Nrf2 Signaling Pathway. Chem Biodivers. 2019 Nov;16(11):e1900400.
Farkhondeh T, et al. The therapeutic effect of resveratrol: Focusing on the Nrf2 signaling pathway. Biomed Pharmacother. 2020 Jul;127:110234.
Ashrafizadeh M, et al. Curcumin Activates the Nrf2 Pathway and Induces Cellular Protection Against Oxidative Injury. Curr Mol Med. 2020;20(2):116-133.
Integrative Pharmacology 
Great headline!
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