Projects per year
Abstract
It is widely accepted that activating the transcription factor NRF2 will blast the physiological anti-inflammatory mechanisms, which will help combat pathologic inflammation. Much effort is being put in inhibiting the main NRF2 repressor, KEAP1, with either electrophilic small molecules or disrupters of the KEAP1/NRF2 interaction. However, targeting β-TrCP, the non-canonical repressor of NRF2, has not been considered yet. After in silico screening of ∼1 million compounds, we now describe a novel small molecule, PHAR, that selectively inhibits the interaction between β-TrCP and the phosphodegron in transcription factor NRF2. PHAR upregulates NRF2-target genes such as Hmox1, Nqo1, Gclc, Gclm and Aox1, in a KEAP1-independent, but β-TrCP dependent manner, breaks the β-TrCP/NRF2 interaction in the cell nucleus, and inhibits the β-TrCP-mediated in vitro ubiquitination of NRF2. PHAR attenuates hydrogen peroxide induced oxidative stress and, in lipopolysaccharide-treated macrophages, it downregulates the expression of inflammatory genes Il1b, Il6, Cox2, Nos2. In mice, PHAR selectively targets the liver and greatly attenuates LPS-induced liver inflammation as indicated by a reduction in the gene expression of the inflammatory cytokines Il1b, TNf, and Il6, and in F4/80-stained liver resident macrophages. Thus, PHAR offers a still unexplored alternative to current NRF2 activators by acting as a β-TrCP/NRF2 interaction inhibitor that may have a therapeutic value against undesirable inflammation.
Original language | English |
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Article number | 102396 |
Number of pages | 17 |
Journal | Redox Biology |
Volume | 55 |
Early online date | 11 Jul 2022 |
DOIs | |
Publication status | Published - Sept 2022 |
Keywords
- Inflammation
- Liver
- NRF2
- Protein-protein interaction inhibitor
- β-TrCP
ASJC Scopus subject areas
- Organic Chemistry
- Clinical Biochemistry
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Dive into the research topics of 'An inhibitor of interaction between the transcription factor NRF2 and the E3 ubiquitin ligase adapter β-TrCP delivers anti-inflammatory responses in mouse liver'. Together they form a unique fingerprint.Projects
- 1 Active
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Defining the Oxidative Stress-Related Mechanisms by which Activation of the Transcription Factor Nrf2 Arrests and Resolves Liver Fibrosis
Arthur, S. (Investigator), Dillon, J. (Investigator), Dinkova-Kostova, A. (Investigator), Hayes, J. (Investigator) & Henderson, C. (Investigator)
1/04/20 → 30/06/25
Project: Research
Research output
- 16 Citations
- 1 Comment/debate
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Corrigendum to "An inhibitor of interaction between the transcription factor NRF2 and the E3 ubiquitin ligase adapter β-TrCP delivers anti-inflammatory responses in mouse liver" [Redox Biol. 55 (2022) 102396/PMID 35839629]: 35839629] (Redox Biology (2022) 55, (S2213231722001689), (10.1016/j.redox.2022.102396))
Fernández-Ginés, R., Encinar, J. A., Hayes, J. D., Oliva, B., Rodríguez-Franco, M. I., Rojo, A. I. & Cuadrado, A. (Lead / Corresponding author), Sept 2022, In: Redox Biology. 55, 1 p., 102428.Research output: Contribution to journal › Comment/debate › peer-review
Open AccessFile1 Citation (Scopus)73 Downloads (Pure)