NRF2 as a guardian of health: from an ancient survival pathway to a modern therapeutic target
17 affiliations
- 1iNOVA4Health, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade Nova de Lisboa, Lisboa, Portugal. Electronic address: [email protected]
- 2iNOVA4Health, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade Nova de Lisboa, Lisboa, Portugal
- 3Institute of Evolutionary Medicine, University of Zurich, Zurich, Switzerland
- 4Centre of Experimental Medicine, Slovak Academy of Sciences, Institute of Normal and Pathological Physiology, Bratislava, Slovakia
- 5Center for Behavioral Sciences and Mental Health, Instituto Superiore di Sanità, Rome, Italy
- 6Department of Biochemistry, Medical College, Autonomous University of Madrid (UAM), Madrid, Spain
- 7Center for Behavioral Sciences and Mental Health, Instituto Superiore di Sanità, Rome, Italy; Faculty of Medicine and Surgery, Catholic University of the Sacred Heart, Rome, Italy
- 8Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Krakow, Poland
- 9Department of Pharmaceutical Sciences, University of Vienna, Vienna, Austria
- 10Malopolska Centre of Biotechnology, Jagiellonian University in Krakow, Krakow, Poland
- 11Institute of Pharmaceutical Science, King's College London, London, United Kingdom; Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, Brazil
- 12Faculty of Medicine, University Hospital Bern, Switzerland
- 13Vienna Airway Lab, Department of Otolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
- 14Department of Physiology and Pharmacology "Vittorio Erspamer", La Sapienza University, Rome, Italy
- 15International Centre for Cancer Vaccine Science, University of Gdansk, Gdansk, Poland
- 16Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
- 17Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
Abstract
NRF2 (Nuclear Factor Erythroid 2-Related Factor 2) has traditionally been viewed as a master regulator of the antioxidant response. However, emerging evidence redefines NRF2 as a pleiotropic and evolutionarily conserved systems-level integrator of redox, metabolic, proteostatic, and inflammatory homeostasis, i.e., an evolutionarily conserved guardian of health. From its origins as an adaptive response to rising atmospheric oxygen in early metazoans to its role in orchestrating complex cytoprotective networks in humans, NRF2 exemplifies the biological transition from stress resistance to adaptive resilience. Understanding its regulation across species, tissues, life stages and gender offers novel perspectives for combating age-related cellular dysfunction and reframing the dynamic process of redox regulation as a component of adaptive homeostasis in a precision medicine perspective. This review summarizes and integrates essential concepts currently being developed regarding the evolutionary roots of NRF2, its molecular and regulatory complexity, its dualistic role in health and disease, and its potential as a biomarker of resilience and therapeutic target. We highlight NRF2's function as a rheostat rather than a binary stress switch, including the role of hormetic activation through lifestyle and environmental stimuli. By maintaining redox homeostasis and dynamic adaptive stress responses, NRF2 bridges molecular defense mechanisms with strategies for healthspan extension and preventive medicine from very early life stages until senescence.
Related
- Functional Roles of Wnt/β-catenin Pathway Components in Pre-Basal Cell Carcinoma-like Cell Proliferation and Survival
- Gene therapy for non-obstructive azoospermia: therapeutic avenues and translational pathway to clinical application
- Glutamine synthesis pathway promotes the survival and recurrence of dormant tumor cells in prostate cancer.
- Editorial: Bioactive and Nutritional Molecules: From Natural Sources to Therapeutic and Health Applications
- FGFBPs in health and tumors: emerging prognostic biomarkers and therapeutic implications
BibTeX
@article{tenreiro2026nrf2,
title = {{NRF2 as a guardian of health: from an ancient survival pathway to a modern therapeutic target}},
author = {Sandra Tenreiro and Ana S. Falcão and Nicole Bender and Iveta Bernátová and Alessandra Berry and Antonio Cuadrado and Patrick Eppenberger and Letizia Giona and Anna Grochot‐Przeczek and Elke H. Heiß and Monika A. Jakubowska and Paul F. Long and Asya Makhro and Mojgan Masoodi and Christina Morgenstern and Luciano Saso and Miguel C. Seabra and Alicja Sznarkowska and Gerasimos Sykiotis and Ioannis P. Trougakos},
journal = {Redox Biology},
year = {2026},
month = may,
doi = {10.1016/j.redox.2026.104217},
url = {https://doi.org/10.1016/j.redox.2026.104217},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - NRF2 as a guardian of health: from an ancient survival pathway to a modern therapeutic target
AU - Sandra Tenreiro
AU - Ana S. Falcão
AU - Nicole Bender
AU - Iveta Bernátová
AU - Alessandra Berry
AU - Antonio Cuadrado
AU - Patrick Eppenberger
AU - Letizia Giona
AU - Anna Grochot‐Przeczek
AU - Elke H. Heiß
AU - Monika A. Jakubowska
AU - Paul F. Long
AU - Asya Makhro
AU - Mojgan Masoodi
AU - Christina Morgenstern
AU - Luciano Saso
AU - Miguel C. Seabra
AU - Alicja Sznarkowska
AU - Gerasimos Sykiotis
AU - Ioannis P. Trougakos
PY - 2026
DA - 2026/05/15
JO - Redox Biology
DO - 10.1016/j.redox.2026.104217
UR - https://doi.org/10.1016/j.redox.2026.104217
AB - NRF2 (Nuclear Factor Erythroid 2-Related Factor 2) has traditionally been viewed as a master regulator of the antioxidant response. However, emerging evidence redefines NRF2 as a pleiotropic and evolutionarily conserved systems-level integrator of redox, metabolic, proteostatic, and inflammatory homeostasis, i.e., an evolutionarily conserved guardian of health. From its origins as an adaptive response to rising atmospheric oxygen in early metazoans to its role in orchestrating complex cytoprotective networks in humans, NRF2 exemplifies the biological transition from stress resistance to adaptive resilience. Understanding its regulation across species, tissues, life stages and gender offers novel perspectives for combating age-related cellular dysfunction and reframing the dynamic process of redox regulation as a component of adaptive homeostasis in a precision medicine perspective. This review summarizes and integrates essential concepts currently being developed regarding the evolutionary roots of NRF2, its molecular and regulatory complexity, its dualistic role in health and disease, and its potential as a biomarker of resilience and therapeutic target. We highlight NRF2's function as a rheostat rather than a binary stress switch, including the role of hormetic activation through lifestyle and environmental stimuli. By maintaining redox homeostasis and dynamic adaptive stress responses, NRF2 bridges molecular defense mechanisms with strategies for healthspan extension and preventive medicine from very early life stages until senescence.
SN - 2213-2317
ER -