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. The NRF2 system originated as an adaptive response to rising atmospheric oxygen in early metazoans (such as porifera and cnidarians). Now it plays a complex role in orchestrating cytoprotective responses in humans, exemplifying the biological transition from stress resistance to adaptive resilience. Understanding the mechanisms underlying the NRF2 fine tuning and the identifications of reliable biomarkers (for the downstream signalling pathways activation) will open new avenues for precision medicine to promote healthy aging.
Tenreiro et al. (2026) studied this question.