Rojo, Ana IButtari, BrigittaSaha, SarmisthaProfumo, ElisabettaCuadrado, AntonioDaiber, AndreasDavinelli, SergioTramutola, AntonellaΧονδρογιάννη, ΝίκηDi Domenico, FabioBerry, AlessandraMiranda, Joana PGiona, LetiziaNuclear 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.Adobe PDF10.3390/biom15010113https://doi.org/10.3390/biom15010113https://hdl.handle.net/10442/192772218-273X39858508eng: © 2025 by the authors. Licensee MDPI, Basel, Switzerland.BiomoleculesNRF2antioxidantsneurodegenerationredox balanceNF-E2-Related Factor 2oxidation-reductionaginganimalsproteostasishumansoxidative stressProteostasis Decline and Redox Imbalance in Age-Related Diseases: The Therapeutic Potential of NRF2Άρθρο σε επιστημονικό περιοδικό2025-01-13Δημοσίευση σε περιοδικόPublication in journalΒιοχημεία και Μοριακή βιολογίαBiochemistry and Molecular Biologyisi - Biochemistry & Molecular Biology covers resources on general biochemistry and molecular biology topics such as carbohydrates, lipids, proteins, nucleic acids, genes, drugs, toxic substances, and other chemical or molecular constituents of cells, microbes, and higher plants and animals, including humans. Excluded are resources that are focus on biochemistry in cells, tissues or organs and those whose primary focus is the organism of study, e.g. plants, microbes, etc. Excluded, also, are resources that focus on methods in biochemistry or molecular biology.Γηριατρική και ΓεροντολογίαGeriatrics and Gerontologyisi - Geriatrics & Gerontology covers resources on the aged and the aging process. This category includes the clinical, biochemical, histological, and psychological aspects of aging. Coverage also includes specific clinical problems in the treatment of elderly patients, as well as research on the cellular and animal correlates of age and senescence. Resources that focus on the psychological, social, and political aspects of aging are covered in the SSCI.Επιστημονικό άρθροScientific articleΕθνικό Ίδρυμα Ερευνών (ΕΙΕ)Greek Aggregator OpenArchives.gr | National Documentation Centre (EKT)