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Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach
Antonio Cuadrado1, Gina Manda2, Ahmed Hassan2
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 (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.) antonio.cuadrado@uam.es emre.guney@upf.edu.
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.
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