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Nrf2/Keap1/ARE signaling: Towards specific regulation

Alexey V Ulasov1, Andrey A Rosenkranz2, Georgii P Georgiev1

  • 1Department of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilov St., 119334 Moscow, Russia.

Life Sciences
|November 4, 2021
PubMed

Insights

The Nrf2-Keap1 pathway regulates cellular defense against oxidative stress. Inhibiting Keap1 can activate Nrf2 for treating diseases like COVID-19, with non-electrophilic inhibitors offering greater specificity.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • The Nrf2 transcription factor controls genes vital for combating oxidative stress, a key factor in diseases like neurodegeneration, cardiovascular conditions, diabetes, and viral infections.
  • Nrf2 activity is primarily regulated by its interaction with the Keap1 protein, which targets Nrf2 for degradation under normal conditions but releases it during oxidative stress to activate protective genes.

Purpose of the Study:

  • To explore the therapeutic potential of activating the Nrf2 system for treating oxidative stress-related diseases, including viral infections like COVID-19.
  • To evaluate strategies for inactivating the Keap1 protein's regulatory function on Nrf2.

Main Methods:

  • Investigating two primary approaches to Nrf2 system activation: modification of Keap1 via electrophilic agents and direct interruption of Nrf2:Keap1 protein-protein interactions (PPI).
  • Comparing the specificity and potential side effects of electrophilic inducers versus non-electrophilic inhibitors of Nrf2:Keap1 PPI.

Main Results:

  • Electrophilic agents targeting Keap1 may cause non-specific interactions with other cellular proteins, potentially leading to adverse effects.
  • Non-electrophilic inhibitors of Nrf2:Keap1 PPI demonstrate higher specificity, suggesting a broader therapeutic window.

Conclusions:

  • Activating the Nrf2 pathway is a promising strategy for treating various pathologies linked to oxidative stress.
  • Non-electrophilic inhibitors of Nrf2:Keap1 PPI represent a potentially safer and more effective therapeutic approach compared to electrophilic inducers.
Keywords:
Influenza virusKeap1Nrf2Oxidative stressROSSARS-CoV-2

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