Proteostasis Decline and Redox Imbalance in Age-Related Diseases: The Therapeutic Potential of NRF2
Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of cellular homeostasis, overseeing the expression of a wide array of genes involved in cytoprotective processes such as antioxidant and proteostasis control, mitochondrial function, inflammation, and the metabolism of lipids a...
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2025-01-01
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| author | Brigitta Buttari Antonella Tramutola Ana I. Rojo Niki Chondrogianni Sarmistha Saha Alessandra Berry Letizia Giona Joana P. Miranda Elisabetta Profumo Sergio Davinelli Andreas Daiber Antonio Cuadrado Fabio Di Domenico |
| author_facet | Brigitta Buttari Antonella Tramutola Ana I. Rojo Niki Chondrogianni Sarmistha Saha Alessandra Berry Letizia Giona Joana P. Miranda Elisabetta Profumo Sergio Davinelli Andreas Daiber Antonio Cuadrado Fabio Di Domenico |
| author_sort | Brigitta Buttari |
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| description | Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of cellular homeostasis, overseeing the expression of a wide array of genes involved in cytoprotective processes such as antioxidant and proteostasis control, mitochondrial function, inflammation, and the metabolism of lipids and glucose. The accumulation of misfolded proteins triggers the release, stabilization, and nuclear translocation of NRF2, which in turn enhances the expression of critical components of both the proteasomal and lysosomal degradation pathways. This process facilitates the clearance of toxic protein aggregates, thereby actively maintaining cellular proteostasis. As we age, the efficiency of the NRF2 pathway declines due to several factors including increased activity of its repressors, impaired NRF2-mediated antioxidant and cytoprotective gene expression, and potential epigenetic changes, though the precise mechanisms remain unclear. This leads to diminished antioxidant defenses, increased oxidative damage, and exacerbated metabolic dysregulation and inflammation—key contributors to age-related diseases. Given NRF2’s role in mitigating proteotoxic stress, the pharmacological modulation of NRF2 has emerged as a promising therapeutic strategy, even in aged preclinical models. By inducing NRF2, it is possible to mitigate the damaging effects of oxidative stress, metabolic dysfunction, and inflammation, thus reducing protein misfolding. The review highlights NRF2’s therapeutic implications for neurodegenerative diseases and cardiovascular conditions, emphasizing its role in improving proteostasis and redox homeostasis Additionally, it summarizes current research into NRF2 as a therapeutic target, offering hope for innovative treatments to counteract the effects of aging and associated diseases. |
| format | Article |
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| institution | Kabale University |
| issn | 2218-273X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj-art-adb6f2b2736b4d8fbbeb8b1cde8e159f2025-01-24T13:25:14ZengMDPI AGBiomolecules2218-273X2025-01-0115111310.3390/biom15010113Proteostasis Decline and Redox Imbalance in Age-Related Diseases: The Therapeutic Potential of NRF2Brigitta Buttari0Antonella Tramutola1Ana I. Rojo2Niki Chondrogianni3Sarmistha Saha4Alessandra Berry5Letizia Giona6Joana P. Miranda7Elisabetta Profumo8Sergio Davinelli9Andreas Daiber10Antonio Cuadrado11Fabio Di Domenico12Department of Cardiovascular and Endocrine-Metabolic Diseases and Aging, Istituto Superiore di Sanità, 00161 Rome, ItalyDepartment of Biochemical Sciences “A. Rossi Fanelli”, Sapienza University, 00185 Rome, ItalyDepartment of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), National Institute of Health Carlos III (ISCIII), Instituto de Investigación Sanitaria La Paz (IdiPaz), 28049 Madrid, SpainInstitute of Chemical Biology, National Hellenic Research Foundation, 116 35 Athens, GreeceDepartment of Biotechnology, Institute of Applied Sciences & Humanities, GLA University, Mathura 00185, Uttar Pradesh, IndiaCenter for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, 00161 Rome, ItalyCenter for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, 00161 Rome, ItalyResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, PortugalDepartment of Cardiovascular and Endocrine-Metabolic Diseases and Aging, Istituto Superiore di Sanità, 00161 Rome, ItalyDepartment of Medicine and Health Sciences “V. Tiberio”, University of Molise, 86100 Campobasso, ItalyDepartment for Cardiology 1, University Medical Center Mainz, Molecular Cardiology, Johannes Gutenberg University, 55131 Mainz, GermanyDepartment of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), National Institute of Health Carlos III (ISCIII), Instituto de Investigación Sanitaria La Paz (IdiPaz), 28049 Madrid, SpainDepartment of Biochemical Sciences “A. Rossi Fanelli”, Sapienza University, 00185 Rome, ItalyNuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of cellular homeostasis, overseeing the expression of a wide array of genes involved in cytoprotective processes such as antioxidant and proteostasis control, mitochondrial function, inflammation, and the metabolism of lipids and glucose. The accumulation of misfolded proteins triggers the release, stabilization, and nuclear translocation of NRF2, which in turn enhances the expression of critical components of both the proteasomal and lysosomal degradation pathways. This process facilitates the clearance of toxic protein aggregates, thereby actively maintaining cellular proteostasis. As we age, the efficiency of the NRF2 pathway declines due to several factors including increased activity of its repressors, impaired NRF2-mediated antioxidant and cytoprotective gene expression, and potential epigenetic changes, though the precise mechanisms remain unclear. This leads to diminished antioxidant defenses, increased oxidative damage, and exacerbated metabolic dysregulation and inflammation—key contributors to age-related diseases. Given NRF2’s role in mitigating proteotoxic stress, the pharmacological modulation of NRF2 has emerged as a promising therapeutic strategy, even in aged preclinical models. By inducing NRF2, it is possible to mitigate the damaging effects of oxidative stress, metabolic dysfunction, and inflammation, thus reducing protein misfolding. The review highlights NRF2’s therapeutic implications for neurodegenerative diseases and cardiovascular conditions, emphasizing its role in improving proteostasis and redox homeostasis Additionally, it summarizes current research into NRF2 as a therapeutic target, offering hope for innovative treatments to counteract the effects of aging and associated diseases.https://www.mdpi.com/2218-273X/15/1/113agingproteostasisNRF2neurodegenerationoxidative stressredox balance |
| spellingShingle | Brigitta Buttari Antonella Tramutola Ana I. Rojo Niki Chondrogianni Sarmistha Saha Alessandra Berry Letizia Giona Joana P. Miranda Elisabetta Profumo Sergio Davinelli Andreas Daiber Antonio Cuadrado Fabio Di Domenico Proteostasis Decline and Redox Imbalance in Age-Related Diseases: The Therapeutic Potential of NRF2 Biomolecules aging proteostasis NRF2 neurodegeneration oxidative stress redox balance |
| title | Proteostasis Decline and Redox Imbalance in Age-Related Diseases: The Therapeutic Potential of NRF2 |
| title_full | Proteostasis Decline and Redox Imbalance in Age-Related Diseases: The Therapeutic Potential of NRF2 |
| title_fullStr | Proteostasis Decline and Redox Imbalance in Age-Related Diseases: The Therapeutic Potential of NRF2 |
| title_full_unstemmed | Proteostasis Decline and Redox Imbalance in Age-Related Diseases: The Therapeutic Potential of NRF2 |
| title_short | Proteostasis Decline and Redox Imbalance in Age-Related Diseases: The Therapeutic Potential of NRF2 |
| title_sort | proteostasis decline and redox imbalance in age related diseases the therapeutic potential of nrf2 |
| topic | aging proteostasis NRF2 neurodegeneration oxidative stress redox balance |
| url | https://www.mdpi.com/2218-273X/15/1/113 |
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