Chemical and Biological Mechanisms of Phytochemical Activation of NRF2 and Importance in Disease Prevention

  • Aimee L. EgglerEmail author
  • Sergey N. Savinov
Part of the Recent Advances in Phytochemistry book series (RAPT, volume 43)


Plants are an incredibly rich source of compounds that activate the Nrf2 transcription factor, leading to upregulation of a battery of cytoprotective genes. This perspective surveys established and proposed molecular mechanisms of Nrf2 activation by phytochemicals with a special emphasis on a common chemical property of Nrf2 activators: the ability as “soft” electrophiles to modify cellular thiols, either directly or as oxidized biotransformants. In addition, the role of reactive oxygen/nitrogen species as secondary messengers in Nrf2 activation is discussed. While the uniquely reactive C151 of Keap1, an Nrf2 repressor protein, is highlighted as a key target of cytoprotective phytochemicals, also reviewed are other stress-responsive proteins, including kinases, which play nonredundant roles in the activation of Nrf2 by plant-derived agents. Finally, the Perspective presents two key factors accounting for the enhanced therapeutic windows of effective phytochemical activators of the Keap1–Nrf2 axis: enhanced selectivity toward sensor cysteines and reversibility of addition to thiolate molecules.


Nrf2 transcription factor Electrophiles Reactive oxygen species Reactive nitrogen species Keap1 Xanthohumol Isoliquiritigenin 10-shogaol Sulforaphane Glutathione Michael acceptors Biotransformation Antioxidant Prooxidant 



We thank Young-Joon Surh, Mark Hannink, Wendy A. Peer, Andrew D. Mesecar, and Albena Dinkova-Kostova for their thoughtful comments on this Perspective. We are grateful to the National Institutes of Health for financial support through the R03 CA128095 grant.


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Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.Department of ChemistryVillanova UniversityVillanovaUSA
  2. 2.Purdue University Center for Cancer ResearchWest LafayetteUSA

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