2024-03-28T16:26:10Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1885832021-07-20T11:30:23Zcom_10261_22com_10261_1col_10261_275
Transcription factor NRF2 as a therapeutic target for chronic diseases: A systems medicine approach
Cuadrado, Antonio
Manda, Gina
Hassan, Ahmed
Alcaraz, María José
Barbas, Coral
Daiber, Andreas
Ghezzi, Pietro
León, Rafael
López, Manuela G.
Oliva, Baldo
Pajares, Marta
Rojo, Ana I.
Robledinos-Antón, Natalia
Valverde, Ángela M.
Guney, Emre
Schmidt, Harald H.H.W.
Ministerio de Economía y Competitividad (España)
Instituto de Salud Carlos III
European Research Council
European Commission
Generalitat Valenciana
Universidad Autónoma de Madrid
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.
This work was supported by Grants SAF2015-71304-REDT, SAF2016-76520-R, SAF2013-4874R, SAF2015-65267-R, and BIO2014-57518 of the Spanish Ministry of Economy and Competiveness; PII4/00372 from the Health Institute Carlos III; PROMETEOII/2014/071 of Generalitat Valenciana; P_37_732/2016 REDBRAIN of the European Regional Development Fund; Competitiveness Operational Program 2014-2020; and the ERC Advanced Grant RadMed 294683 and COST action 15120 OpenMultiMed (H.H.H.W.S.). M.P. is the recipient of a FPU fellowship of Autonomous University of Madrid. E.G. is supported by a European-cofunded Beatriu de Pinos fellowship. R.L. is supproted by the Miguel Servet II fellow (CPII16/00014).
Peer reviewed
2019-08-20T10:11:42Z
2019-08-20T10:11:42Z
2018
artículo
http://purl.org/coar/resource_type/c_6501
Pharmacological Reviews 70(2): 348-383 (2018)
0031-6997
http://hdl.handle.net/10261/188583
10.1124/pr.117.014753
1521-0081
http://dx.doi.org/10.13039/501100003359
http://dx.doi.org/10.13039/501100003329
http://dx.doi.org/10.13039/501100004593
http://dx.doi.org/10.13039/501100004587
http://dx.doi.org/10.13039/501100000781
http://dx.doi.org/10.13039/501100000780
29507103
en
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info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2015-71304-REDT
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016-76520-R
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2013-4874R,
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2015-65267-R
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BIO2014-57518-R
info:eu-repo/grantAgreement/EC/FP7/294683
Publisher's version
https://doi.org/10.1124/pr.117.014753
Sí
open
American Society for Pharmacology and Experimental Therapeutics