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Nrf2 (nuclear factor erythroid 2-related factor 2) is a cellular protein that regulates the expression of antioxidant and stress response proteins. It participates in the Keap1/Nrf2/ARE biological pathway – the primary mechanism by which sulforaphane exerts its beneficial effects. A 2017 review describes the role of sulforaphane in the Keap1/Nrf2/ARE pathway and summarizes the beneficial health effects associated with the compound.

The Keap1/Nrf2/ARE pathway is a key mediator of cytoprotective responses to oxidative and electrophilic stressors. Under normal cellular conditions, Keap1 tethers Nrf2 in the cytoplasm (the region of the cell outside the nucleus), where it can be tagged and delivered for degradation. However, following exposure to stressors, Keap1 undergoes modifications that impair its ability to bind to and target Nrf2 for degradation. As a result, Nrf2 is free to travel to the nucleus, where it binds to antioxidant response elements (AREs) of DNA. AREs are sequences in the regulatory regions of genes that activate transcription of a diverse group of cytoprotective enzymes.

Isothiocyanates react with certain regions on Keap1, eliminating Keap1’s ability to target Nrf2 for degradation – effectively serving the role of stressor. Sulforaphane, an isothiocyanate derived from broccoli and broccoli sprouts, is the most potent naturally occurring inducer of Nrf2.

The authors of the review presented evidence that sulforaphane protects against carcinogenesis in models of skin, oral, stomach, colon, lung, prostate, and bladder cancer. They also reported that feeding studies involving humans and consumption of isothiocyanate-rich cruciferous vegetables have demonstrated measurable Nrf2 activity, reflected in increased levels antioxidant proteins and enzymes, including glutathione S-transferase and NQO1. Future research will inform optimal dosages and formulations for clinical trials.

Watch this clip in which Dr. Jed Fahey describes the early co-discoveries of sulforaphane and Nrf2 and describes the importance of the Nrf2 pathway.

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