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    Nrf2 - The Most Important Signaling Pathway In The Body?

    Nrf2 - The Most Important Signaling Pathway In The Body?

    NRF2 is a transcription factor that is activated by oxidative stress. It is a key regulator of the antioxidant response. Nrf2 = The Antioxidant Master Switch. Calorie restriction, exercise, phytochemicals, intermittent fasting, cold exposure and heat all activate it. Read more below!

    Nrf2 (nuclear factor erythroid-derived 2 like protein) is a transcription factor commonly found in a cell’s cytoplasm. It activates the transcription of over 500 genes in the human genome. When Nrf2 is activated it goes into the nucleus to perform its main functions. It binds to the antioxidant response elements (ARE) located in the promoter region of genes encoding many phase II detoxifying or antioxidant enzymes and related stress-responsive proteins.

    Nrf2 - The Most Important Signaling Pathway In Body?

    Image source: Northwest life Science Specialties.

    Under normal conditions, Nrf2 is repressed by Keap1, which is an adaptor protein for the degradation of Nrf2. But during oxidative stress, Nrf2 is derepressed (or activated) and this activates the transcription of protective genes. The Keap1-Nrf2 system plays a role in inflammation-associated pathogenesis.

    The Nrf2 signaling pathway and its subsequent induction of cytoprotective (protection of cells from harmful agents) protein expression is the main cellular defense mechanism against oxidative and electrophilic stress. Therefore, interactions of Nrf2 with other signaling components regulate the efficiency of the cellular stress response. One of these is autophagy (read a comprehensive article on autophagy here).

    The health benefits of Nrf2 are for example:

    Lifestyle factors that activate Nrf2

    Lifestyle and other factors activating Nrf2 include heat and cold exposure¬† ‚Äď when practiced in one session as heat alteration may produce the best results (see a specific article on Heat Alteration). Physical exercise is also a known Nrf2 activator. For example acute aerobic exercise elicits activation of nuclear Nrf2, regardless of exercise intensity. But higher-intensity exercise results in greater activity of glutathione reductase.

    Nrf2 signaling in sedentary older adults can also be restored to a degree with moderate exercise training. To conclude, episodic increases in oxidative stress induced through bouts of acute exercise stimulate Nrf2 activation and when applied repeatedly, it leads to upregulation of endogenous antioxidant defenses and overall greater ability to fight oxidative stress.

    Other lifestyle factors increasing Nrf2 include fasting, calorie restriction, and the activation of ketosis (check Biohacker's Guide to Ketosis here). It should be also mentioned that well functioning mitochondria also almost automatically means a well-functioning Nrf2 signaling. It is also known that loss of Nrf2 leads to impaired mitochondrial function.

    Nutritional factors supporting Nrf2

    There are multiple nutritional compounds and components that support the function and activation of Nrf2. Several natural antioxidants have emerged as possible Nrf2 pathway activators amongst which chalcones are very active ones. Chalcones constitute an important group of natural compounds that are especially abundant in fruits (e.g., citruses, apples), vegetables (e.g., tomatoes, shallots, bean sprouts, potatoes) and various plants and spices (e.g., licorice),‚ÄĒmany of which have been used for centuries in traditional herbal medicine. They activate Nrf2 signaling pathway, expression of Nrf2-regulated antioxidant genes, induce cytoprotective proteins and upregulate multidrug resistance-associated proteins.

    Nrf2 - The Most Important Signaling Pathway In Body?

    Image: Multi-target interaction of chalcones on cross-talk between Nrf2 and NF-őļB response pathways involved in inflammation.

    Source: de Freitas Silva, M. et al. (2018). The Keap1/Nrf2-ARE pathway as a pharmacological target for chalcones. Molecules 23 (7): 1803.

    Chalcone compound



    A flavonoid precursor


    Humulus lupulus or Hops

    Licochalcone E 

    Licorice root

    Safflor Yellow A

    Various yellow colored foods

    Lophirones B & C

    Lophira lanceolata or dwarf red ironwood


    Licorice root


    Licorice root


    Helichrysum arenarium or dwarf everlast flowers


    Various foods such as cocoa, Greek oregano, sour orange, grapefruit etc.


    Alpinia katsumadai & Alpinia conchigera


    Various plants such as Butea dahlia, Coreopsis and Searsia

    HMC (Hesperidin methyl chalcone)

    Citrus fruits, especially in their peels, such as orange peels

    Flawokawains A, B & C

    Piper methysticum (Kava-kava)


    Nrf2 - The Most Important Signaling Pathway In Body?

    Image: Main polyphenol family members.

    Source: Orlikova, B. & Tasdemir, D. & Golais, F. & Dicato, M. & Diederich, M. (2011). Dietary chalcones with chemopreventive and chemotherapeutic potential. Genes & Nutrition 6 (2): 125‚Äď147.

    Flavonoids can be further divided into various subclasses of which chalcones, flavonols, flavones, flavanones, anthocyanidins, and isoflavonoids are the most common. See a comprehensive list of flavonoids in Biohacker’s Handbook’s Nutrition Chapter.

    Other foods and compounds that are known to activate Nrf2:


    Have you heard of Nrf2 before? What did you learn reading this article? Tell us in the comments!

    Order our new book here: the Resilient Being.

    comment 1 kommentti

    Laura calendar_today

    I am forever grateful for Nrf2 activation!! I have been taking an Nrf2 activator for almost 8 years now!! More potent than any single ingredient like resveritrol, silymarin, or turmeric it’s is a synergistic compound with loads of published science behind it!! Everyone needs to know about this!! Thanks for sharing

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