Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

doi:10.1124/pr.117.014753

Review

. 2018 Apr;70(2):348-383.

doi: 10.1124/pr.117.014753.

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

Antonio Cuadrado¹, Gina Manda², Ahmed Hassan², María José Alcaraz², Coral Barbas², Andreas Daiber², Pietro Ghezzi², Rafael León², Manuela G López², Baldo Oliva², Marta Pajares², Ana I Rojo², Natalia Robledinos-Antón², Angela M Valverde², Emre Guney¹, Harald H H W Schmidt²

Affiliations

¹ Centro 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 (Autonomous University of Madrid)-CSIC (Centro Superior de Investigaciones Biomédicas), Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., M.P., A.I.R., N.R.-A.); Victor Babes National Institute of Pathology, Bucharest, Romania (A.C., G.M.); Department Pharmacology and Personalized Medicine, School for Cardiovascular Medicine, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastrich, The Netherlands (A.H., H.H.H.W.S.); Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico, Universitat Politècnica de València, Universitat de València, Valencia, Spain (M.J.A.); Centre for Metabolomics and Bioanalysis, Facultad de Farmacia, Universidad CEU (Centro de Estudios Universitarios)-San Pablo, Madrid, Spain (C.B.); Center for Cardiology, Cardiology I-Laboratory of Molecular Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany (A.D.); Brighton and Sussex Medical School, Brighton, United Kingdom (P.G.); Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain (R.L., M.G.L.); Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, Madrid, Spain (R.L., M.G.L.); GRIB (Unidad de Investigación en Informática Biomédica), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain (B.O., E.G.); Instituto de Investigaciones Biomédicas Alberto Sols UAM-CSIC and Centro de Investigación Biomédica en Red en Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain (A.M.V.); and Structural Bioinformatics Laboratory, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain (E.G.) [email protected] [email protected].
² Centro 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 (Autonomous University of Madrid)-CSIC (Centro Superior de Investigaciones Biomédicas), Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., M.P., A.I.R., N.R.-A.); Victor Babes National Institute of Pathology, Bucharest, Romania (A.C., G.M.); Department Pharmacology and Personalized Medicine, School for Cardiovascular Medicine, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastrich, The Netherlands (A.H., H.H.H.W.S.); Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico, Universitat Politècnica de València, Universitat de València, Valencia, Spain (M.J.A.); Centre for Metabolomics and Bioanalysis, Facultad de Farmacia, Universidad CEU (Centro de Estudios Universitarios)-San Pablo, Madrid, Spain (C.B.); Center for Cardiology, Cardiology I-Laboratory of Molecular Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany (A.D.); Brighton and Sussex Medical School, Brighton, United Kingdom (P.G.); Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain (R.L., M.G.L.); Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, Madrid, Spain (R.L., M.G.L.); GRIB (Unidad de Investigación en Informática Biomédica), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain (B.O., E.G.); Instituto de Investigaciones Biomédicas Alberto Sols UAM-CSIC and Centro de Investigación Biomédica en Red en Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain (A.M.V.); and Structural Bioinformatics Laboratory, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain (E.G.).

PMID: 29507103
DOI: 10.1124/pr.117.014753

Free article

Review

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

Antonio Cuadrado et al. Pharmacol Rev. 2018 Apr.

Free article

. 2018 Apr;70(2):348-383.

doi: 10.1124/pr.117.014753.

Authors

Affiliations

¹ Centro 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 (Autonomous University of Madrid)-CSIC (Centro Superior de Investigaciones Biomédicas), Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., M.P., A.I.R., N.R.-A.); Victor Babes National Institute of Pathology, Bucharest, Romania (A.C., G.M.); Department Pharmacology and Personalized Medicine, School for Cardiovascular Medicine, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastrich, The Netherlands (A.H., H.H.H.W.S.); Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico, Universitat Politècnica de València, Universitat de València, Valencia, Spain (M.J.A.); Centre for Metabolomics and Bioanalysis, Facultad de Farmacia, Universidad CEU (Centro de Estudios Universitarios)-San Pablo, Madrid, Spain (C.B.); Center for Cardiology, Cardiology I-Laboratory of Molecular Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany (A.D.); Brighton and Sussex Medical School, Brighton, United Kingdom (P.G.); Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain (R.L., M.G.L.); Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, Madrid, Spain (R.L., M.G.L.); GRIB (Unidad de Investigación en Informática Biomédica), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain (B.O., E.G.); Instituto de Investigaciones Biomédicas Alberto Sols UAM-CSIC and Centro de Investigación Biomédica en Red en Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain (A.M.V.); and Structural Bioinformatics Laboratory, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain (E.G.) [email protected] [email protected].
² Centro 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 (Autonomous University of Madrid)-CSIC (Centro Superior de Investigaciones Biomédicas), Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., M.P., A.I.R., N.R.-A.); Victor Babes National Institute of Pathology, Bucharest, Romania (A.C., G.M.); Department Pharmacology and Personalized Medicine, School for Cardiovascular Medicine, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastrich, The Netherlands (A.H., H.H.H.W.S.); Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico, Universitat Politècnica de València, Universitat de València, Valencia, Spain (M.J.A.); Centre for Metabolomics and Bioanalysis, Facultad de Farmacia, Universidad CEU (Centro de Estudios Universitarios)-San Pablo, Madrid, Spain (C.B.); Center for Cardiology, Cardiology I-Laboratory of Molecular Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany (A.D.); Brighton and Sussex Medical School, Brighton, United Kingdom (P.G.); Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain (R.L., M.G.L.); Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, Madrid, Spain (R.L., M.G.L.); GRIB (Unidad de Investigación en Informática Biomédica), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain (B.O., E.G.); Instituto de Investigaciones Biomédicas Alberto Sols UAM-CSIC and Centro de Investigación Biomédica en Red en Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain (A.M.V.); and Structural Bioinformatics Laboratory, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain (E.G.).

PMID: 29507103
DOI: 10.1124/pr.117.014753

Abstract

Systems medicine has a mechanism-based rather than a symptom- or organ-based approach to disease and identifies therapeutic targets in a nonhypothesis-driven manner. In this work, we apply this to transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) by cross-validating its position in a protein-protein interaction network (the NRF2 interactome) functionally linked to cytoprotection in low-grade stress, chronic inflammation, metabolic alterations, and reactive oxygen species formation. Multiscale network analysis of these molecular profiles suggests alterations of NRF2 expression and activity as a common mechanism in a subnetwork of diseases (the NRF2 diseasome). This network joins apparently heterogeneous phenotypes such as autoimmune, respiratory, digestive, cardiovascular, metabolic, and neurodegenerative diseases, along with cancer. Importantly, this approach matches and confirms in silico several applications for NRF2-modulating drugs validated in vivo at different phases of clinical development. Pharmacologically, their profile is as diverse as electrophilic dimethyl fumarate, synthetic triterpenoids like bardoxolone methyl and sulforaphane, protein-protein or DNA-protein interaction inhibitors, and even registered drugs such as metformin and statins, which activate NRF2 and may be repurposed for indications within the NRF2 cluster of disease phenotypes. Thus, NRF2 represents one of the first targets fully embraced by classic and systems medicine approaches to facilitate both drug development and drug repurposing by focusing on a set of disease phenotypes that appear to be mechanistically linked. The resulting NRF2 drugome may therefore rapidly advance several surprising clinical options for this subset of chronic diseases.

PubMed Disclaimer

Cited by

Demystifying Oxidative Stress.
Ghezzi P, Mooradian AD. Ghezzi P, et al. Handb Exp Pharmacol. 2021;264:3-26. doi: 10.1007/164_2020_379. Handb Exp Pharmacol. 2021. PMID: 32767143
Antioxidant Defence Systems and Oxidative Stress in Poultry Biology: An Update.
Surai PF, Kochish II, Fisinin VI, Kidd MT. Surai PF, et al. Antioxidants (Basel). 2019 Jul 22;8(7):235. doi: 10.3390/antiox8070235. Antioxidants (Basel). 2019. PMID: 31336672 Free PMC article. Review.
The Role of Nrf2 in the Antioxidant Cellular Response to Medical Ozone Exposure.
Galiè M, Covi V, Tabaracci G, Malatesta M. Galiè M, et al. Int J Mol Sci. 2019 Aug 17;20(16):4009. doi: 10.3390/ijms20164009. Int J Mol Sci. 2019. PMID: 31426459 Free PMC article. Review.
Ferroptosis-modulating small molecules for targeting drug-resistant cancer: Challenges and opportunities in manipulating redox signaling.
Koeberle SC, Kipp AP, Stuppner H, Koeberle A. Koeberle SC, et al. Med Res Rev. 2023 May;43(3):614-682. doi: 10.1002/med.21933. Epub 2023 Jan 19. Med Res Rev. 2023. PMID: 36658724 Free PMC article. Review.
Aging, NRF2, and TAU: A Perfect Match for Neurodegeneration?
Brackhan M, Arribas-Blazquez M, Lastres-Becker I. Brackhan M, et al. Antioxidants (Basel). 2023 Aug 4;12(8):1564. doi: 10.3390/antiox12081564. Antioxidants (Basel). 2023. PMID: 37627559 Free PMC article. Review.

See all "Cited by" articles

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions

LinkOut - more resources

Full Text Sources
Other Literature Sources
- The Lens - Patent Citations Database
- scite Smart Citations
Medical
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

Affiliations

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

Authors

Affiliations

Abstract

Similar articles

Cited by

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Abstract

Similar articles

Cited by

Publication types

MeSH terms

Substances

Related information

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical