NRF2 as a ferroptosis gatekeeper in colorectal cancer: implications for therapy

Colorectal cancer (CRC) is one of the primary cancer concerns for global health, with high incidence and mortality rates worldwide. The natural history of CRC is a complicated and multistep process characterized by genetic alterations with various biological features, including genomic instability, excessive cell proliferation, angiogenesis, and metastasis. This review focuses on the delicate interaction between ferroptosis, a recently unveiled form of iron-dependent cell death, the nuclear factor erythroid 2-related factor 2 (NRF2), an important transcriptional factor that controls the pharmacology of oxidative stress and cellular metabolism in the context of CRC. NRF2 is critical for regulating the cells' antioxidant response to compensate for the damage caused by reactive oxygen species and maintain iron homeostasis. By this, NRF2 would function as a negative regulator of ferroptosis, which could be an undesirable process for tumour cells if induced. Certainly, NRF2 activities lower the levels of ROS and manipulate the labile iron pool (LIP). The relationship between NRF2 and ferroptosis is further complicated by the actions of a downstream gene, HO-1, whose expression is regulated by NRF2. NRF2 promotes the transcription of glutathione peroxidase 4 (GPX4) and SLC7A11 (a component of the cystine/glutamate antiporter system Xc⁻). It also regulates iron metabolism by upregulating genes such as ferritin heavy chain (FTH1) and ferroportin (FPN), thus further suppressing ferroptosis. Mounting evidence suggests that targeting the NRF2-ferroptosis axis by Tagitinin C, Lysionotin, Ginsenoside Rh3, Cetuximab, Esculin, Brassinin, and Angelic acid could open up novel therapeutic avenues for treating colorectal cancer, thereby improving CRC patient outcomes and overall survival.