Targeting NRF2 Driven Pathways in Cancer: Mechanisms of Resistance and Therapeutic Opportunities

Abstract

NRF2's intricate role within cancer is continually developing, with its function as a transcription factor extending to the regulation of genes responsible for maintaining redox balance, protein homeostasis, lipid and iron metabolism, proliferation, and survival. Herein, we highlight NRF2's pivotal involvement in cellular responses to several downstream stressful pathways, its regulatory mechanisms, and its impact on health and disease, notably in cancer. Complementary to this, the study uncovers NRF2-mediated p97 upregulation, shedding light on its implications for protein homeostasis and redox balance. Furthermore, investigations into NRF2's influence on chronic arsenic-induced carcinogenesis provide crucial insights. The second facet of the research confronts these mechanisms further, proposing innovative strategies such as NRF2 and p97 co-inhibition as a therapeutic approach. Additionally, the exploration of NRF2's involvement in modulating ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, unveils novel insights into NRF2's broader impact beyond classical antioxidant responses. Furthermore, the study extends its scope to development of targeted synthetic nanobodies against SLC7A11, a crucial component of the ferroptosis pathway. Meanwhile, leveraging advanced techniques such as the NRF2 crystal structure analysis of the Neh1-MafG-ARE complex provides valuable insights for NRF2 targeted precision drug design. Taken together, these findings expand our understanding of NRF2-related pathways in mechanisms of cancer resistance and offer promising avenues for innovative therapeutic strategies harnessing the NRF2 axis against cancer and drug resistance challenges.