RT Journal Article
SR Electronic
T1 Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach
JF Pharmacological Reviews
JO Pharmacol Rev
FD American Society for Pharmacology and Experimental Therapeutics
SP 348
OP 383
DO 10.1124/pr.117.014753
VO 70
IS 2
A1 Cuadrado, Antonio
A1 Manda, Gina
A1 Hassan, Ahmed
A1 Alcaraz, María José
A1 Barbas, Coral
A1 Daiber, Andreas
A1 Ghezzi, Pietro
A1 León, Rafael
A1 López, Manuela G.
A1 Oliva, Baldo
A1 Pajares, Marta
A1 Rojo, Ana I.
A1 Robledinos-Antón, Natalia
A1 Valverde, Angela M.
A1 Guney, Emre
A1 Schmidt, Harald H. H. W.
A2 Michel, Martin C.
YR 2018
UL http://pharmrev.aspetjournals.org/content/70/2/348.abstract
AB 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.