Nrf2 Is a Potential Modulator for Orchestrating Iron Homeostasis and Redox Balance in Cancer Cells

Abstract

Iron is an essential trace mineral element in almost all living cells and organisms. However, cellular iron metabolism pathways are disturbed in most cancer cell types. Cancer cells have a high demand of iron. To maintain rapid growth and proliferation, cancer cells absorb large amounts of iron by altering expression of iron metabolism related proteins. However, iron can catalyze the production of reactive oxygen species (ROS) through Fenton reaction. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is an important player in the resistance to oxidative damage by inducing the transcription of antioxidant genes. Aberrant activation of Nrf2 is observed in most cancer cell types. It has been revealed that the over-activation of Nrf2 promotes cell proliferation, suppresses cell apoptosis, enhances the self-renewal capability of cancer stem cells, and even increases the chemoresistance and radioresistance of cancer cells. Recently, several genes involving cellular iron homeostasis are identified under the control of Nrf2. Since cancer cells require amounts of iron and Nrf2 plays pivotal roles in oxidative defense and iron metabolism, it is highly probable that Nrf2 is a potential modulator orchestrating iron homeostasis and redox balance in cancer cells. In this hypothesis, we summarize the recent findings of the role of iron and Nrf2 in cancer cells and demonstrate how Nrf2 balances the oxidative stress induced by iron through regulating antioxidant enzymes and iron metabolism. This hypothesis provides new insights into the role of Nrf2 in cancer progression. Since ferroptosis is dependent on lipid peroxide and iron accumulation, Nrf2 inhibition may dramatically increase sensitivity to ferroptosis. The combination of Nrf2 inhibitors with ferroptosis inducers may exert greater efficacy on cancer therapy.

Lipoxin A4 attenuates MSU-crystal-induced NLRP3 inflammasome activation through suppressing Nrf2 thereby increasing TXNRD2

“…Nrf2 has a crucial protective role in inflammation under oxidative stress and is a widely recognized antioxidant butler ( 21 ). The activated Nrf2 can promote antioxidant protein expression and trigger related antioxidant systems to exert its antioxidant function ( 43 , 44 , 51 ). The activation of Nrf2 is considered the chief measure of some cell protectors developing antioxidant effects and subsequent anti-inflammatory roles ( 51 ).…”

“…Nrf2 is a classical and pivotal regulator with an antioxidant role (43)(44)(45). LXA4 can arouse Nrf2 activation to mediate antioxidant and anti-inflammatory activity (17)(18)(19).…”

Ferroptosis and ferritinophagy in diabetes complications

“…When stimulated by oxidative damage, NRF2 separates from Keap1 and enters the nucleus to boost the expression of downstream target genes [ 69 ]. In terms of mechanism, NRF2 reduces the damage that oxidative stress causes by regulating antioxidant enzymes and iron metabolism [ 70 ]. Since the ferroptosis process is also dependent on the accumulation of lipid peroxide and iron, the inhibition of NRF2 may significantly increase the sensitivity to ferroptosis [ 70 ].…”

NRF2 and Mitochondrial Function in Cancer and Cancer Stem Cells

“…In the case of mitochondrial ferritin, it may have protective effects in the inhibition of ferroptosis [ 116 ]. CISD1, an iron-containing outer mitochondrial membrane protein, was shown to interact with NRF2-mediated transcription to prevent mitochondrial injury during ferroptosis [ 117 ]. The pathway p62–NRF2 was shown to be involved in the resistance of cancer cells to ferroptosis under GPX4 inhibition [ 118 ].…”