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Transcription factor NRF2 as a therapeutic target for chronic diseases: a systems medicine approach

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posted on 2023-06-09, 12:37 authored by Antonio Cuadrado, Gina Manda, Ahmed Hassan, María José Alcaraz, Coral Barbas, Andreas Daiber, Pietro Ghezzi, Rafael León, Manuela G López, Baldo Oliva, Marta Pajares, Ana I Rojo, Natalia Robledinos-Antón, Angela M Valverde, Emre Guney, Harald H H W Schmidt
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.

History

Publication status

  • Published

File Version

  • Published version

Journal

Pharmacological reviews

ISSN

1521-0081

Publisher

American Society for Pharmacology and Experimental Therapeutics

Issue

2

Volume

70

Page range

348-383

Department affiliated with

  • Clinical and Experimental Medicine Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2018-03-26

First Open Access (FOA) Date

2018-03-26

First Compliant Deposit (FCD) Date

2018-03-26

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