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

Antonio Cuadrado*, Gina Manda, Ahmed Hassan, Maria Alcaraz, Coral Barbas, Andreas Daiber, Pietro Ghezzi, Rafael Leon, Manuela G. Lopez, Baldo Oliva, Marta Pajares, Ana I. Rojo, Natalia Robledinos-Anton, Angela M. Valverde, Emre Guney*, Harald H. H. W. Schmidt

*Corresponding author for this work

Research output: Contribution to journal(Systematic) Review article peer-review

289 Citations (Web of Science)

Abstract

Systems medicine has a mechanism-based rather than a symptom-or organ-basedapproach 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.
Original languageEnglish
Pages (from-to)348-383
Number of pages36
JournalPharmacological Reviews
Volume70
Issue number2
DOIs
Publication statusPublished - 1 Apr 2018

Keywords

  • NF-KAPPA-B
  • PROTEIN-PROTEIN INTERACTION
  • FUMARIC-ACID ESTERS
  • EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS
  • TYPE-2 DIABETES-MELLITUS
  • GLYCOGEN-SYNTHASE KINASE
  • TUMOR-SUPPRESSOR PTEN
  • HEME OXYGENASE 1
  • GENE PROMOTER POLYMORPHISM
  • PLACEBO-CONTROLLED PHASE-3

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