Altered NRF2 Signalling in Systemic Redox Imbalance: Insights From Non-Communicable Diseases

Abstract

The balanced activity of the cytoprotective transcription factor NRF2 is central for maintaining redox, metabolicenergetics, and proteome homeostasis, as well as for regulating inflammatory responses, among other functions. Activated NRF2 regulates the expression of hundreds of genes containing antioxidant response elements (AREs) or electrophile response elements (EpRE) in their regulatory regions, often promoting cytoprotection under stress conditions and contributing to defence against various pathologies and non-communicable diseases (NCDs). The products of increased NRF2 activity, detected systemically, may originate from either the white blood cells, the cells of the vasculature or tissue-derived products that could be secreted into biological fluids. Therefore, assessing basal and inducible NRF2 activity in blood or other biofluids is crucial for inferring NRF2 responses in local and often inaccessible tissues. In previous work, we identified a panel of six biomarkers - Glutamatecysteine ligase catalytic subunit (GCLC), Glutamate-cysteine ligase modifier subunit (GCLM), Haem oxygenase 1 (HMOX1), NAD(P)H quinone dehydrogenase 1 (NQO1), Sulfiredoxin 1 (SRXN1), and Thioredoxin reductase 1 (TXNRD1) - as indicators of NRF2 activity. In the current study, we assess their utility in a clinical setting to measure NRF2 activation in a disease context. Here we discuss findings on how NRF2 activity in accessible human samples can reveal its involvement in various NCDs and its connection to clinical aspects such as diagnosis, disease progression and response to therapy.COST (European Cooperation in Science and Technology) [ZI28TVQ2F1]This article is based upon work from COST Action CA20121-Bench to bedside transition for pharmacological regulation of NRF2 in non-communicable diseases (BenBedPhar) benbedphar.org, supported by COST (European Cooperation in Science and Technology, www.cost.eu). Fig. 1 was created in https://BioRender.com. Fig. 4 was created in EM>STRONG> /STRONG>/EM>BioRender under agreement number: PL28CWK3PN (Jakubowska, M. (2025) https://BioRender.com/iez2dgy), and Fig. 7 under agreement number: ZI28TVQ2F1 (Jakubowska, M. (2025) https://BioRender.co m/a4kbrtz)