{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T21:14:14Z","timestamp":1789161254341,"version":"build-2803163510"},"reference-count":238,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:00:00Z","timestamp":1768521600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004504","name":"Research Council of Lithuania","doi-asserted-by":"crossref","award":["S-A-UEI-23-7"],"award-info":[{"award-number":["S-A-UEI-23-7"]}],"id":[{"id":"10.13039\/501100004504","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>This review summarizes the role of nuclear factor erythroid 2\u2013related factor 2 (Nrf2) as a common link between aging, neurodegeneration, and neuropathic pain. Aging is characterized by oxidative stress and constant inflammation, which coincides with reduced Nrf2 activity and weaker antioxidant responses, increasing vulnerability to diseases. In neurodegenerative disorders\u2014including Alzheimer\u2019s, Parkinson\u2019s, Huntington\u2019s disease, and amyotrophic lateral sclerosis\u2014evidence indicates that impaired Nrf2 signaling contributes to oxidative damage, neuroinflammation, and mitochondrial dysfunction. Furthermore, in neuropathic pain, similar mechanisms are involved, and Nrf2 could play a role as a potential analgesic target because of its role in regulating cellular defense pathways. We also review natural Nrf2 modulators (e.g., flavonoids, other polyphenols, terpenoids, alkaloids), discussing their benefits alongside common translational limitations such as poor solubility, low oral bioavailability, rapid metabolism, and potential safety issues, including possible pro-oxidant effects and chemoresistance. We also outline future directions that should prioritize improving delivery systems, addressing NRF2\/KEAP1 gene variations, evaluating combinations with standard therapies, exploring preventive applications, and defining dosing, treatment duration, and long-term safety. Overall, current evidence indicates that Nrf2 modulation is a practical, cross-cutting approach relevant to healthy aging and disease management.<\/jats:p>","DOI":"10.3390\/pharmaceutics18010118","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:27:53Z","timestamp":1768570073000},"page":"118","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Nrf2 Modulation by Natural Compounds in Aging, Neurodegeneration, and Neuropathic Pain"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1744-2932","authenticated-orcid":false,"given":"Jurga","family":"Bernatoniene","sequence":"first","affiliation":[{"name":"Department of Drug Technology and Social Pharmacy, Faculty of Pharmacy, Medical Academy, Lithuanian University of Health Sciences, Sukileliu Pr. 13, LT-50161 Kaunas, Lithuania"},{"name":"Institute of Pharmaceutical Technologies, Faculty of Pharmacy, Medical Academy, Lithuanian University of Health Sciences, Sukileliu Pr. 13, LT-50161 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3399-2849","authenticated-orcid":false,"given":"Dalia M.","family":"Kopustinskiene","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Technologies, Faculty of Pharmacy, Medical Academy, Lithuanian University of Health Sciences, Sukileliu Pr. 13, LT-50161 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5511-6831","authenticated-orcid":false,"given":"Roberto","family":"Casale","sequence":"additional","affiliation":[{"name":"OPUSMEDICA Persons, Care & Research-NPO, 29121 Piacenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6285-607X","authenticated-orcid":false,"given":"Alessandro","family":"Medoro","sequence":"additional","affiliation":[{"name":"Department of Medicine and Health Sciences \u201cV. Tiberio\u201d, University of Molise, 86100 Campobasso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2578-7199","authenticated-orcid":false,"given":"Sergio","family":"Davinelli","sequence":"additional","affiliation":[{"name":"Department of Medicine and Health Sciences \u201cV. Tiberio\u201d, University of Molise, 86100 Campobasso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4530-8706","authenticated-orcid":false,"given":"Luciano","family":"Saso","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology \u201cVittorio Erspamer\u201d, La Sapienza University, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kestutis","family":"Petrikonis","sequence":"additional","affiliation":[{"name":"Department of Neurology, Lithuanian University of Health Sciences, Eiveni\u0173 Str. 2, LT-50009 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,16]]},"reference":[{"key":"ref_1","first-page":"1477","article-title":"Transcription Factor Nrf2 and Mitochondria\u2014Friends or Foes in the Regulation of Aging Rate","volume":"87","author":"Shilovsky","year":"2022","journal-title":"Biochemistry"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Cominelli, G., Sulas, F., Pinto, D., Rinaldi, F., Favero, G., and Rezzani, R. 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