Transcription Factor NRF2 as a Therapeutic Target for Bipolar Disorders: A Systems Medicine Approach
Systems medicine has a mechanism-based rather than a symptom- or – organ-based approach to disease and explains therapeutic goals in a nonhypothesis-driven manner. In this function, we employ 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 those molecular profiles indicates alterations of NRF2 expression and action as a frequent mechanism in a subnetwork of ailments (the NRF2 diseasome). This system joins apparently heterogeneous phenotypes like autoimmune, respiratory, digestive, cardiovascular, metabolic, and neurodegenerative diseases, along with cancer. Significantly, this approach matches and confirms in silico several applications for NRF2-modulating drugs supported in vivo at different stages of clinical improvement. 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 enrolled medications such as metformin and statins, which trigger NRF2 and may be repurposed for signs within the NRF2 cluster of disease phenotypes. Thus, NRF2 represents among the first targets fully embraced by classic and systems medication approaches to facilitate both drug development and drug repurposing by focusing on a group of disease phenotypes that appear to be mechanistically linked. The consequent NRF2 drugome may consequently rapidly advance several sudden clinical options for this subset of chronic diseases.