The Intricacies of NRF2 Regulation in Cancer

Abstract The complex role of NRF2 in the context of cancer continues to evolve. As a transcription factor, NRF2 regulates various genes involved in redox homeostasis, protein degradation, DNA repair, and xenobiotic metabolism. As such, NRF2 is critical in preserving cell function and viability, particularly during stress. Importantly, NRF2 itself is regulated via a variety of mechanisms, and the mode of NRF2 activation often dictates the duration of NRF2 signaling and its role in either preventing cancer initiation or promoting cancer progression. Herein, different modes of NRF2 regulation, including oxidative stress, autophagy dysfunction, protein-protein interactions, and epigenetics, as well as pharmacological modulators targeting this cascade in cancer, are explored. Specifically, how the timing and duration of these different mechanisms of NRF2 induction affect tumor initiation, progression, and metastasis are discussed. Additionally, progress in the discovery and development of NRF2 inhibitors for the treatment of NRF2-addicted cancers is highlighted, including modulators that inhibit specific NRF2 downstream targets. Overall, a better understanding of the intricate nature of NRF2 regulation in specific cancer contexts should facilitate the generation of novel therapeutics designed to not only prevent tumor initiation, but also halt progression and ultimately improve patient wellbeing and survival.