NRF2: Master regulator of cellular homeostasis and therapeutic vulnerability in cancer

The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is best known for its regulation of the antioxidant response. However, its mediation of other pathways, including key aspects of metabolic and protein homeostasis, has continued to emerge. Accompanying this emergence is an evolved understanding that NRF2 induction across different disease contexts can be beneficial or detrimental depending on the length of activation. This has played an important role in progressing the field forward, as inducing NRF2 is not always the best course of action, and inhibition has gained traction as a viable strategy for treating cancer and other pathologies where NRF2 is chronically active. Despite its rapid growth and a wealth of experimental promise, a persistent shortcoming in the field is a lack of NRF2-specific therapeutics used in clinic. Thus, despite recent advances, there is still room for progress in translating experimental evidence into therapeutic reality. In this review, we will provide a summary of NRF2 regulation and an update on its expanded network of downstream transcriptional programs. We will also discuss targeting NRF2 in disease, focusing on intervention versus prevention depending on the pathological context. Finally, we will briefly highlight current limitations in the field, as well as ongoing approaches that show promise for finally targeting this critical cascade in patient populations.