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Review
. 2024 Jun:72:103134.
doi: 10.1016/j.redox.2024.103134. Epub 2024 Mar 30.

Biomarkers of NRF2 signalling: Current status and future challenges

Christina Morgenstern  1 , Isabel Lastres-Becker  2 , Birsen Can Demirdöğen  3 , Vera Marisa Costa  4 , Andreas Daiber  5 , Roberta Foresti  6 , Roberto Motterlini  6 , Sibel Kalyoncu  7 , Burak I Arioz  8 , Sermin Genc  9 , Monika Jakubowska  10 , Ioannis P Trougakos  11 , Aleksandra Piechota-Polanczyk  12 , Michel Mickael  13 , Marlene Santos  14 , Thomas W Kensler  15 , Antonio Cuadrado  2 , Ian M Copple  16
Affiliations
Review

Biomarkers of NRF2 signalling: Current status and future challenges

Christina Morgenstern et al. Redox Biol. 2024 Jun.

Abstract

The cytoprotective transcription factor NRF2 regulates the expression of several hundred genes in mammalian cells and is a promising therapeutic target in a number of diseases associated with oxidative stress and inflammation. Hence, an ability to monitor basal and inducible NRF2 signalling is vital for mechanistic understanding in translational studies. Due to some caveats related to the direct measurement of NRF2 levels, the modulation of NRF2 activity is typically determined by measuring changes in the expression of one or more of its target genes and/or the associated protein products. However, there is a lack of consensus regarding the most relevant set of these genes/proteins that best represents NRF2 activity across cell types and species. We present the findings of a comprehensive literature search that according to stringent criteria identifies GCLC, GCLM, HMOX1, NQO1, SRXN1 and TXNRD1 as a robust panel of markers that are directly regulated by NRF2 in multiple cell and tissue types. We assess the relevance of these markers in clinically accessible biofluids and highlight future challenges in the development and use of NRF2 biomarkers in humans.

Keywords: Biomarker; NRF2; Oxidative stress response; Target genes; Transcription factor.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ian Copple reports article publishing charges was provided by European Cooperation in Science and Technology. Ian Copple reports financial support was provided by the Medical Research Council. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
The NRF2 signalling pathway. Under basal conditions, a KEAP1/CUL3/RBX1 complex binds to NRF2 and promotes its ubiquitination and subsequent proteasomal degradation. In addition, NRF2 can be regulated via glycogen synthase kinase 3β (GSK-3β) mediated phosphorylation, which promotes ubiquitination of the transcription factor by a β-TrCP/CUL1/RBX1 complex. Upon activation of NRF2 by electrophiles, reactive oxygen species (ROS) and other stimuli, NRF2 evades these repression mechanisms, accumulates in the nucleus, and modulates the expression of several hundred cytoprotective genes.
Fig. 2
Fig. 2
Frequency of citations for the panel of NRF2 biomarkers. The stacked bar chart shows the unique count of references falling within the defined criteria for each of the selected genes/proteins. (Diagram was drawn with R 4.2.1 and RStudio version 2023.12.0 + 369 making use of ggplot2 library.)
See this image and copyright information in PMC

References

    1. Itoh K., Chiba T., Takahashi S., Ishii T., Igarashi K., Katoh Y., Oyake T., Hayashi N., Satoh K., Hatayama I., Yamamoto M., Nabeshima Y. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem. Biophys. Res. Commun. 1997;236:313–322. doi: 10.1006/bbrc.1997.6943. - DOI - PubMed
    1. Itoh K., Igarashi K., Hayashi N., Nishizawa M., Yamamoto M. Cloning and characterization of a novel erythroid cell-derived CNC family transcription factor heterodimerizing with the small Maf family proteins. Mol. Cell Biol. 1995;15:4184–4193. doi: 10.1128/MCB.15.8.4184. - DOI - PMC - PubMed
    1. Itoh K., Wakabayashi N., Katoh Y., Ishii T., Igarashi K., Engel J.D., Yamamoto M. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 1999;13:76–86. doi: 10.1101/gad.13.1.76. - DOI - PMC - PubMed
    1. Tong K.I., Padmanabhan B., Kobayashi A., Shang C., Hirotsu Y., Yokoyama S., Yamamoto M. Different electrostatic potentials define ETGE and DLG motifs as hinge and latch in oxidative stress response. Mol. Cell Biol. 2007;27:7511–7521. doi: 10.1128/MCB.00753-07. - DOI - PMC - PubMed
    1. Hayes J.D., Dinkova-Kostova A.T. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem. Sci. 2014;39:199–218. doi: 10.1016/j.tibs.2014.02.002. - DOI - PubMed

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