A novel β-TrCP1/NRF2 interaction inhibitor for effective anti-inflammatory therapy
Background Non-communicable chronic diseases are characterized by low-grade inflammation and oxidative stress. Extensive research has identified the transcription factor NRF2 as a potential therapeutic target. Current NRF2 activators, designed to inhibit its repressor KEAP1, often exhibit undesirabl...
| Autores: | , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Universidad Autónoma de Madrid |
| Repositorio: | Biblos-e Archivo. Repositorio Institucional de la UAM |
| Idioma: | inglés |
| OAI Identifier: | oai:repositorio.uam.es:10486/728500 |
| Acceso en línea: | https://hdl.handle.net/10486/728500 https://dx.doi.org/10.1186/s12929-025-01157-3 |
| Access Level: | acceso abierto |
| Palabra clave: | NRF2 β-TrCP1 Protein–protein interaction-inhibitor Inflammation Liver Medicina Química |
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| dc.title.none.fl_str_mv |
A novel β-TrCP1/NRF2 interaction inhibitor for effective anti-inflammatory therapy |
| title |
A novel β-TrCP1/NRF2 interaction inhibitor for effective anti-inflammatory therapy |
| spellingShingle |
A novel β-TrCP1/NRF2 interaction inhibitor for effective anti-inflammatory therapy García Yagüe, Ángel Juan NRF2 β-TrCP1 Protein–protein interaction-inhibitor Inflammation Liver Medicina Química |
| title_short |
A novel β-TrCP1/NRF2 interaction inhibitor for effective anti-inflammatory therapy |
| title_full |
A novel β-TrCP1/NRF2 interaction inhibitor for effective anti-inflammatory therapy |
| title_fullStr |
A novel β-TrCP1/NRF2 interaction inhibitor for effective anti-inflammatory therapy |
| title_full_unstemmed |
A novel β-TrCP1/NRF2 interaction inhibitor for effective anti-inflammatory therapy |
| title_sort |
A novel β-TrCP1/NRF2 interaction inhibitor for effective anti-inflammatory therapy |
| dc.creator.none.fl_str_mv |
García Yagüe, Ángel Juan Cañizares Moscato, Lucía Encinar, José Antonio Cazalla Ibáñez, Eduardo Fernández Ginés, Raquel Escoll, Maribel Rojo Sanchís, Ana Isabel Cuadrado Pastor, Antonio |
| author |
García Yagüe, Ángel Juan |
| author_facet |
García Yagüe, Ángel Juan Cañizares Moscato, Lucía Encinar, José Antonio Cazalla Ibáñez, Eduardo Fernández Ginés, Raquel Escoll, Maribel Rojo Sanchís, Ana Isabel Cuadrado Pastor, Antonio |
| author_role |
author |
| author2 |
Cañizares Moscato, Lucía Encinar, José Antonio Cazalla Ibáñez, Eduardo Fernández Ginés, Raquel Escoll, Maribel Rojo Sanchís, Ana Isabel Cuadrado Pastor, Antonio |
| author2_role |
author author author author author author author |
| dc.contributor.none.fl_str_mv |
Departamento de Bioquímica Facultad de Medicina Gobierno de España Comunidad de Madrid |
| dc.subject.none.fl_str_mv |
NRF2 β-TrCP1 Protein–protein interaction-inhibitor Inflammation Liver Medicina Química |
| topic |
NRF2 β-TrCP1 Protein–protein interaction-inhibitor Inflammation Liver Medicina Química |
| description |
Background Non-communicable chronic diseases are characterized by low-grade inflammation and oxidative stress. Extensive research has identified the transcription factor NRF2 as a potential therapeutic target. Current NRF2 activators, designed to inhibit its repressor KEAP1, often exhibit undesirable side effects. As an alternative approach, we previously developed PHAR, a protein–protein interaction inhibitor of β-TrCP1/NRF2, which promotes NRF2 activation. Using the same in silico screening platform, we have now identified a novel compound, P10. This small molecule selectively interferes with the β-TrCP1/NRF2 interaction, leading to NRF2 stabilization and transcriptional activation of its target genes in a β-TrCP1-dependent manner, demonstrating promising effects in a liver model of acute inflammation. Methods After an in silico screening of ∼1 million compounds, including molecular docking analysis, ADMET evaluation, and molecular dynamics simulations, we identified and characterized a novel small molecule, P10, which inhibits β-TrCP1/NRF2 interaction. The compound was validated using luciferase reporter assays, co-immunoprecipitation, and ubiquitination experiments. The specificity of P10 was assessed by comparing NRF2 signatures in wild-type and Nrf2-null cells. The impact of NRF2 activation induced by P10 was investigated by evaluating its antioxidant and anti-inflammatory responses against tert-butyl hydroperoxide and lipopolysaccharide, respectively. Finally, wild-type and Nrf2-null mice were administered P10 intraperitoneally at a dose of 20 mg/kg daily for five consecutive days. Four hours before sacrifice, all animals received a lipopolysaccharide (LPS) injection at 10 mg/kg. Results P10 selectively disrupts the interaction between β-TrCP1 and NRF2, thereby inhibiting β-TrCP1-mediated ubiquitination of NRF2 and leading to the upregulation of NRF2 target genes. Additionally, P10 mitigates oxidative stress induced by tert-butyl hydroperoxide and reduces pro-inflammatory markers in an NRF2-dependent manner in macrophages treated with lipopolysaccharide. In a preclinical model of liver inflammation, P10 specifically targets the liver, significantly attenuating lipopolysaccharide-induced inflammation through the activation of NRF2. This is demonstrated by decreased expression of inflammatory cytokine genes and a reduction in F4/80-stained liver macrophages. Notably, this anti-inflammatory effect is absent in Nrf2-knockout mice, confirming its NRF2-dependent mechanism of action. Conclusions P10 emerges as a promising NRF2 activator by selectively disrupting the β-TrCP1/NRF2 interaction, highlighting its potential as a therapeutic agent for diseases presenting acute liver inflammation |
| publishDate |
2025 |
| dc.date.none.fl_str_mv |
2025 2025-07-11 |
| dc.type.none.fl_str_mv |
research article http://purl.org/coar/resource_type/c_2df8fbb1 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85 |
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info:eu-repo/semantics/article |
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article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/10486/728500 https://dx.doi.org/10.1186/s12929-025-01157-3 40646550 |
| url |
https://hdl.handle.net/10486/728500 https://dx.doi.org/10.1186/s12929-025-01157-3 |
| identifier_str_mv |
40646550 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ |
| dc.rights.openaire.fl_str_mv |
info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ |
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openAccess |
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application/pdf |
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Springer Nature |
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Springer Nature |
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reponame:Biblos-e Archivo. Repositorio Institucional de la UAM instname:Universidad Autónoma de Madrid |
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Universidad Autónoma de Madrid |
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Biblos-e Archivo. Repositorio Institucional de la UAM |
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Biblos-e Archivo. Repositorio Institucional de la UAM |
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1869422439980597248 |
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A novel β-TrCP1/NRF2 interaction inhibitor for effective anti-inflammatory therapyGarcía Yagüe, Ángel JuanCañizares Moscato, LucíaEncinar, José AntonioCazalla Ibáñez, EduardoFernández Ginés, RaquelEscoll, MaribelRojo Sanchís, Ana IsabelCuadrado Pastor, AntonioNRF2β-TrCP1Protein–protein interaction-inhibitorInflammationLiverMedicinaQuímicaBackground Non-communicable chronic diseases are characterized by low-grade inflammation and oxidative stress. Extensive research has identified the transcription factor NRF2 as a potential therapeutic target. Current NRF2 activators, designed to inhibit its repressor KEAP1, often exhibit undesirable side effects. As an alternative approach, we previously developed PHAR, a protein–protein interaction inhibitor of β-TrCP1/NRF2, which promotes NRF2 activation. Using the same in silico screening platform, we have now identified a novel compound, P10. This small molecule selectively interferes with the β-TrCP1/NRF2 interaction, leading to NRF2 stabilization and transcriptional activation of its target genes in a β-TrCP1-dependent manner, demonstrating promising effects in a liver model of acute inflammation. Methods After an in silico screening of ∼1 million compounds, including molecular docking analysis, ADMET evaluation, and molecular dynamics simulations, we identified and characterized a novel small molecule, P10, which inhibits β-TrCP1/NRF2 interaction. The compound was validated using luciferase reporter assays, co-immunoprecipitation, and ubiquitination experiments. The specificity of P10 was assessed by comparing NRF2 signatures in wild-type and Nrf2-null cells. The impact of NRF2 activation induced by P10 was investigated by evaluating its antioxidant and anti-inflammatory responses against tert-butyl hydroperoxide and lipopolysaccharide, respectively. Finally, wild-type and Nrf2-null mice were administered P10 intraperitoneally at a dose of 20 mg/kg daily for five consecutive days. Four hours before sacrifice, all animals received a lipopolysaccharide (LPS) injection at 10 mg/kg. Results P10 selectively disrupts the interaction between β-TrCP1 and NRF2, thereby inhibiting β-TrCP1-mediated ubiquitination of NRF2 and leading to the upregulation of NRF2 target genes. Additionally, P10 mitigates oxidative stress induced by tert-butyl hydroperoxide and reduces pro-inflammatory markers in an NRF2-dependent manner in macrophages treated with lipopolysaccharide. In a preclinical model of liver inflammation, P10 specifically targets the liver, significantly attenuating lipopolysaccharide-induced inflammation through the activation of NRF2. This is demonstrated by decreased expression of inflammatory cytokine genes and a reduction in F4/80-stained liver macrophages. Notably, this anti-inflammatory effect is absent in Nrf2-knockout mice, confirming its NRF2-dependent mechanism of action. Conclusions P10 emerges as a promising NRF2 activator by selectively disrupting the β-TrCP1/NRF2 interaction, highlighting its potential as a therapeutic agent for diseases presenting acute liver inflammationThis research was funded by the Spanish Ministry of Economy and Competitiveness (MINECO) (grants PDC2021-121421-I00, PDC2022-1337665-I00, PID2022-141786OB-I00, and PID2019-110061RB-I00). The Autonomous Community of Madrid (grants S2017BMD-3827 and P2022_BMD-7230). EC is the holder of an FPU contract of MIU (Ministry of Universities FPU2021, FPU21/02505)Springer NatureDepartamento de BioquímicaFacultad de MedicinaGobierno de EspañaComunidad de Madrid20252025-07-11research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10486/728500https://dx.doi.org/10.1186/s12929-025-01157-340646550reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/7285002026-06-23T12:46:27Z |
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15.811543 |