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Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

Antonio Cuadrado1,2, Ana I Rojo1,2, Geoffrey Wells3

  • 1Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry and Instituto de Investigaciones Biomédicas Alberto Sols UAM-CSIC, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain.

Nature Reviews. Drug Discovery
|January 6, 2019
PubMed

Insights

The NRF2-KEAP1 pathway regulates cellular homeostasis and protects against disease. While activators show promise, challenges in specificity, efficacy, and safety persist for therapeutic development.

Area of Science:

  • Molecular Biology
  • Cellular Homeostasis
  • Disease Pathophysiology

Background:

  • The transcription factor NRF2 (encoded by NFE2L2) and its regulator KEAP1 are crucial for maintaining redox, metabolic, and protein balance.
  • NRF2 activation confers cytoprotection against various chronic diseases, including lung and liver conditions, autoimmune disorders, neurodegeneration, metabolic diseases, and cancer initiation.

Purpose of the Study:

  • To review the role of the NRF2-KEAP1 pathway in cellular homeostasis and disease.
  • To discuss the therapeutic potential of NRF2 activators and KEAP1 modulators.
  • To highlight the existing challenges in the clinical development of these agents.

Main Methods:

  • Literature review of NRF2 and KEAP1 function.
  • Analysis of current therapeutic strategies targeting the NRF2-KEAP1 pathway.
  • Discussion of clinical development challenges.

Main Results:

  • NRF2 activation is a key mechanism for cytoprotection against a wide range of pathologies.
  • Several NRF2 activators and KEAP1 inhibitors are in clinical development, with one activator already approved.
  • Challenges remain concerning target specificity, pharmacodynamics, efficacy, and safety.

Conclusions:

  • The NRF2-KEAP1 pathway represents a significant therapeutic target for numerous diseases.
  • Further research and development are needed to overcome current limitations for effective and safe clinical application.

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