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The Keap1/Nrf2 pathway in health and disease: from the bench to the clinic

Maria A O'Connell1, John D Hayes2

  • 1School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, U.K. m.oconnell@uea.ac.uk.

Biochemical Society Transactions
|November 10, 2015
PubMed

Insights

Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is a key regulator of cellular antioxidant responses. Its complex regulation and therapeutic potential in various diseases are increasingly recognized, making it a significant drug target.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is a master regulator of the antioxidant response.
  • Its role in physiological and pathological processes like redox signaling, metabolism, and aging is widely acknowledged.
  • Nrf2 is implicated in cellular adaptation to stress, drug metabolism, inflammation, and neurodegeneration.

Purpose of the Study:

  • To highlight the complex regulatory mechanisms of Nrf2.
  • To underscore the growing therapeutic interest in Nrf2 modulation for various diseases.
  • To review the cross-talk of Nrf2 with other signaling pathways.

Main Methods:

  • Literature review focusing on Nrf2 regulation and function.
  • Analysis of Nrf2's interaction with key signaling pathways like Keap1, GSK-3/β-TrCP, and NF-κB.
  • Examination of Nrf2's role in disease pathogenesis and therapeutic strategies.

Main Results:

  • Nrf2 regulation involves intricate cross-talk with multiple signaling pathways beyond Keap1.
  • Pathways such as GSK-3/β-TrCP, Hrd1, NF-κB, Notch, and AMP kinase influence Nrf2 activity.
  • Nrf2's involvement spans diverse processes including chemoprevention, chemoresistance, toxicity, and aging.

Conclusions:

  • Nrf2 is a crucial target for therapeutic intervention due to its beneficial roles in disease.
  • Modulating the Nrf2 pathway holds promise for treating conditions related to oxidative stress and inflammation.
  • Ongoing research focuses on developing novel small molecules to target the Nrf2 pathway in clinical trials.
Keywords:
Kelch-like ECH-associated protein-1 (Keap1)cytoprotectionnuclear factor-erythroid 2 p45-related factor 2 (Nrf2)redoxsignallingstress

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