Thirty years of NRF2: advances and therapeutic challenges

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. Advances in understanding the mechanistic regulation of NRF2 and its roles in human pathology have propelled the investigation of NRF2-targeted therapeutic strategies. This Review dissects the mechanistic intricacies of NRF2 signalling, its cross-talk with biological processes and its far-reaching implications for health and disease, highlighting key discoveries that have shaped innovative therapeutic approaches targeting NRF2. Since its discovery 30 years ago, NRF2 has emerged as a master regulator of cellular homeostasis and has been implicated in a broad range of pathologies. This Review analyses NRF2 regulation, signalling and cross-talk, and assesses the role of this transcription factor in health and disease. The development of therapeutic NRF2 modulators and the associated challenges are also discussed.