Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach
Open accessAbstract
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.
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Nrf2 is a transcription factor that controls the expression of over 200 genes involved in antioxidant defence, xenobiotic metabolism, inflammation regulation and mitochondrial biogenesis.
“Nrf2 is a transcription factor that controls the expression of over 200 genes involved in antioxidant defence, xenobiotic metabolism, inflammation regulation and mitochondrial biogenesis [59].”
From Ignoring the planet: A critical blind spot for research on ageing (2025) · cites this paper as [59]
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- Authors
- Cuadrado, A., Manda, G., Hassan, A., Alcaraz, M. J., Barbas, C., Daiber, A., Ghezzi, P., León, R., López, M. G., Oliva, B., Pajares, M., Rojo, A. I., Robledinos-Antón, N., Valverde, A. M., Guney, E., & Schmidt, H. H. H. W.
- Affiliations
- Universitat de València (ES)
- ORCID
- Venue
- Pharmacological Reviews
- Publisher
- Elsevier BV
- Published
- 2018-04
- Volume
- 70
- Issue
- 2
- Pages
- 348-383
- ISSN
- 0031-6997 (ISSN-L)
- OpenAlex
- W2790475021
- Cited by
- 632
- References
- 27
- Citations by year
- 2026: 48 · 2025: 65 · 2024: 83 · 2023: 73 · 2022: 102 · 2021: 83 · 2020: 88 · 2019: 66 · 2018: 21 · 2014: 1
- FWCI
- 6.40
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Pharmacological Reviews (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, cc-by-nc)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion)
- RECERCAT (Consorci de Serveis Universitaris de Catalunya) (publishedVersion, other-oa)
- Tesis Doctorals en Xarxa (Consorci de Serveis Universitaris de Catalunya) (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
- Sussex Research Online (University of Sussex) (submittedVersion, cc-by)
- Figshare (submittedVersion, cc-by)
- Hispana (submittedVersion)
- CINECA IRIS Institutional Research information system (University of Urbino) (submittedVersion)
- Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by-nc)
- Biblos-e Archivo (Universidad Autónoma de Madrid) (submittedVersion, public-domain)
- RiuNet (Universitat Politècnica de València) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- Generalitat Valenciana (PROMETEOII/2014/071)
- European Regional Development Fund (P_37_732/2016 REDBRAIN, 2014-2020’, P_37_732, SAF2016-76520-R, P_37_732/2016, SAF2013-4874R)
- FP7 Ideas: European Research Council (294683)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- Nrf2, drug repurposing, chronic disease, protein-protein interaction network, reactive oxygen species, chronic inflammation, metabolic disorders, neurodegenerative diseases, cancer, dimethyl fumarate, bardoxolone methyl, sulforaphane, metformin, statins, electrophilic compounds
- MeSH terms
- Animals, Anti-Inflammatory Agents, Chronic Disease, Humans, Systems Analysis, NF-E2-Related Factor 2, Drug Discovery, Drug Repositioning, Molecular Targeted Therapy
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