The Roles of NRF2 in Modulating Cellular Iron Homeostasis

Abstract

Significance: Iron and oxygen are intimately linked: iron is an essential nutrient utilized as a cofactor in enzymes for oxygen transport, oxidative phosphorylation, and metabolite oxidation. However, excess labile iron facilitates the formation of oxygen-derived free radicals capable of damaging biomolecules. Therefore, biological utilization of iron is a tightly regulated process. The nuclear factor (erythroid-derived 2)-like 2 (NRF2) transcription factor, which can respond to oxidative and electrophilic stress, regulates several genes involved in iron metabolism.Recent Advances: The bulk of NRF2 transcription factor research has focused on its roles in detoxification and cancer prevention. Recent works have identified that several genes involved in heme synthesis, hemoglobin catabolism, iron storage, and iron export are under the control of NRF2. Constitutive NRF2 activation and subsequent deregulation of iron metabolism have been implicated in cancer development: NRF2-mediated upregulation of the iron storage protein ferritin or heme oxygenase 1 can lead to enhanced proliferation and therapy resistance. Of note, NRF2 activation and alterations to iron signaling in cancers may hinder efforts to induce the iron-dependent cell death process known as ferroptosis.Critical Issues: Despite growing recognition of NRF2 as a modulator of iron signaling, exactly how iron metabolism is altered due to NRF2 activation in normal physiology and in pathologic conditions remains imprecise; moreover, the roles of NRF2-mediated iron signaling changes in disease progression are only beginning to be uncovered.Future Directions: Further studies are necessary to connect NRF2 activation with physiological and pathological changes to iron signaling and oxidative stress.

Single-cell RNA-sequencing of Herpes simplex virus 1-infected cells identifies NRF2 activation as an antiviral program

“…Whereas SULF1 was previously shown to be induced by TNFα in MRC-5 fibroblasts [33], we found no clear activators for OXTR, but indications that proinflammatory cytokines such as IL-1β, IL-6, and TNFα might induce its transcription [34]. For the activation of NQO1 and the correlating genes FTH1, FTL, and SQSTM1, several reports pointed to the transcription factor NFE2L2 (also known as NRF2) [35][36][37].…”

Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

“…Additionally, genes encoding proteins responsible for glutathione synthesis, including SLC7A11, GCLC/GLCM, and GSS are NRF2 target genes (Kerins and Ooi, 2017). …”

Alterations of redox and iron metabolism accompany development of HIV latency

“…Inside cells, iron can be found in its ferric (Fe(III) or ferrous (Fe(II) forms, with the latter being reactive and capable of promoting oxidative stress through the Fenton reaction (Wang & Pantopoulos 2011) . The storage and export of iron are directly controlled by Nrf2, which regulates the ferritin H (FTH-1) iron storage molecule as well as the ferroportin (SLC40A1) iron exporter (Kerins & Ooi 2018;Muckenthaler et al 2017) . Altered levels of the iron import protein, transferrin receptor 1 (TfR1, encoded by TFRC ) have been reported upon HIV-1 infection, and increased or decreased iron levels have been associated with enhanced or reduced viral replication, respectively, albeit only in cell lines (Savarino, Pescarmona, et al 1999;Savarino, Calosso, et al 1999;Drakesmith & Prentice 2008) .…”