TY - JOUR T1 - Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach JF - Pharmacological Reviews JO - Pharmacol Rev SP - 348 LP - 383 DO - 10.1124/pr.117.014753 VL - 70 IS - 2 AU - Antonio Cuadrado AU - Gina Manda AU - Ahmed Hassan AU - María José Alcaraz AU - Coral Barbas AU - Andreas Daiber AU - Pietro Ghezzi AU - Rafael León AU - Manuela G. López AU - Baldo Oliva AU - Marta Pajares AU - Ana I. Rojo AU - Natalia Robledinos-Antón AU - Angela M. Valverde AU - Emre Guney AU - Harald H. H. W. Schmidt A2 - Michel, Martin C. Y1 - 2018/04/01 UR - http://pharmrev.aspetjournals.org/content/70/2/348.abstract N2 - 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. ER -