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Role of the Nrf2 signaling system in health and disease

B M Hybertson1, B Gao

  • 1Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Clinical Genetics
|August 8, 2014
PubMed

Insights

Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates cytoprotective genes. Dysregulation of Nrf2/Keap1/ARE signaling, either too low or too high, drives interest in developing Nrf2 activators and inhibitors for novel therapies.

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Gene Regulation

Background:

  • Nuclear factor erythroid 2-related factor 2 (Nrf2) is crucial for cytoprotective gene regulation.
  • Nrf2 is normally degraded by Kelch-like ECH-associated inhibitor 1 (Keap1), but stress stabilizes it.
  • Activated Nrf2 binds antioxidant response elements (AREs) to control protective genes.

Purpose of the Study:

  • To explore the dual role of Nrf2 in cytoprotection and disease.
  • To highlight the therapeutic potential of modulating Nrf2/Keap1/ARE signaling.
  • To underscore the need for both Nrf2 activators and inhibitors.

Main Methods:

  • Review of Nrf2 pathway regulation under normal and stress conditions.
  • Analysis of Nrf2's role in cancer cell proliferation and drug resistance.
  • Examination of therapeutic strategies targeting the Nrf2 pathway.

Main Results:

  • Nrf2 activation promotes beneficial gene expression but can drive cancer growth and resistance when constitutively active.
  • Mutations leading to constitutive Nrf2 activation confer advantages to tumor cells.
  • Imbalances in Nrf2/Keap1/ARE signaling are implicated in various pathologies.

Conclusions:

  • The Nrf2 pathway presents a complex target for therapeutic intervention.
  • Developing both activators and inhibitors of Nrf2 is essential for treating diverse conditions.
  • Targeting Nrf2 offers promising avenues for novel cancer therapies and cytoprotective treatments.
Keywords:
Keap1Nrf2antioxidantoxidative stress

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