Thirty years of NRF2: advances and therapeutic challenges
Donna D. Zhang
Abstract
Over the last 30 years, NRF2 has evolved from being recognized as a transcription factor primarily involved in redox balance and detoxification to a well-appreciated master regulator of cellular proteostasis, metabolism and iron homeostasis. NRF2 plays a pivotal role in diverse pathologies, including cancer, and metabolic, inflammatory and neurodegenerative disorders. It exhibits a Janus-faced duality, safeguarding cellular integrity in normal cells against environmental insults to prevent disease onset, whereas in certain cancers, constitutively elevated NRF2 levels provide a tumour survival advantage, promoting progression, therapy resistance and metastasis.
Key Findings
- NRF2 has evolved from a redox/detoxification factor to a master regulator of cellular proteostasis, metabolism, and iron homeostasis
- NRF2 exhibits 'Janus-faced duality' — protective in normal cells but tumour-promoting in cancer
- One NRF2 activator has clinical approval; several KEAP1 modifiers are in clinical development
- Comprehensive review of 30 years of NRF2 research from leading authority
Clinical Significance
Landmark review establishing the current state of the field. Highlights that NRF2 is now recognized far beyond its original antioxidant role, with critical implications for cancer therapy, neurodegeneration, and metabolic disease.
Citation
Zhang, D.D. (2025). Thirty years of NRF2: advances and therapeutic challenges. Nature Reviews Drug Discovery.