{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T10:14:54Z","timestamp":1775124894412,"version":"3.50.1"},"reference-count":54,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: The valorization of bioactive compounds from food industry by-products aligns with sustainable development goals and represents a strategy for obtaining functional ingredients. Hazelnut (Corylus avellana L.) skins are a phenolic-rich residue with high antioxidant potential, but their extraction conditions and cellular mechanisms of action remain insufficiently explored. Methods: Ultrasound-assisted extraction was optimized using a 33 Full Factorial Design (FFD) by investigating temperature (30\u201350\u201370 \u00b0C), extraction time (1\u20132\u20133 h), and solvent composition (water\/ethanol). Antioxidant activity was evaluated using multiple in vitro assays, including Total Phenolic Content (TPC), DPPH, ABTS, FRAP, and \u03b2-carotene bleaching (BCB) assays. The optimized extract (OE) was chemically characterized by UHPLC\u2013MS\/MS and its activity was evaluated in HepG2 cells for biocompatibility, modulation of intracellular ROS levels, and antioxidant pathway activation. Results: Optimal extraction conditions were identified as 30 \u00b0C, 70.86 min (1.181 h), and 21.13% ethanol (v\/v), yielding an extract with enhanced antioxidant capacity. UHPLC\u2013MS\/MS analysis revealed 25 bioactive compounds, mainly flavonoids and phenolic acids, relevant for oxidative stress modulation. The extract significantly reduced tert-butyl hydroperoxide (TBH)-induced intracellular ROS levels, restoring antioxidant proteins involved in the Nuclear Factor erythroid 2-related factor 2 (NRF-2)-mediated defense pathway. Conclusions: The optimized hazelnut skin extract combines strong antioxidant efficacy with cellular compatibility, supporting its potential application as a functional ingredient for nutraceutical and pharmaceutical strategies targeting oxidative stress-related conditions.<\/jats:p>","DOI":"10.3390\/ph19040539","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T14:33:33Z","timestamp":1774622013000},"page":"539","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Technological Optimization and Antioxidant Efficacy via the NRF-2-Mediated Defense Pathway of Corylus avellana L. Skin Extracts: A Sustainable Approach for Developing Health-Promoting Natural Products"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5274-8633","authenticated-orcid":false,"given":"Immacolata","family":"Faraone","sequence":"first","affiliation":[{"name":"Department of Health Sciences, University of Basilicata, Via dell\u2019Ateneo Lucano 10, 85100 Potenza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2145-0284","authenticated-orcid":false,"given":"Maria","family":"Ponticelli","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University of Basilicata, Via dell\u2019Ateneo Lucano 10, 85100 Potenza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7999-1502","authenticated-orcid":false,"given":"Claudia","family":"Mangieri","sequence":"additional","affiliation":[{"name":"Department of Basic and Applied Sciences, University of Basilicata, Via dell\u2019Ateneo Lucano 10, 85100 Potenza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1132-8056","authenticated-orcid":false,"given":"Ilaria","family":"Nigro","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University of Basilicata, Via dell\u2019Ateneo Lucano 10, 85100 Potenza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7011-7288","authenticated-orcid":false,"given":"Ludovica","family":"Lela","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University of Basilicata, Via dell\u2019Ateneo Lucano 10, 85100 Potenza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7937-3309","authenticated-orcid":false,"given":"Antonio","family":"Vassallo","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University of Basilicata, Via dell\u2019Ateneo Lucano 10, 85100 Potenza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5599-8187","authenticated-orcid":false,"given":"Carlo","family":"Cosentino","sequence":"additional","affiliation":[{"name":"Department of Agriculture, Forest, Food and Environmental Sciences, University of Basilicata, Via dell\u2019Ateneo Lucano 10, 85100 Potenza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8482-0481","authenticated-orcid":false,"given":"Nikolay T.","family":"Tzvetkov","sequence":"additional","affiliation":[{"name":"Department of Biochemical Pharmacology & Drug Design, Institute of Molecular Biology \u201cRoumen Tsanev\u201d, Bulgarian Academy of Sciences, Acad. 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Bonchev Str., Bl. 21, 1113 Sofia, Bulgaria"},{"name":"Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05-552 Magdalenka, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3954-0170","authenticated-orcid":false,"given":"Vittorio","family":"Carlucci","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University of Basilicata, Via dell\u2019Ateneo Lucano 10, 85100 Potenza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5607-5288","authenticated-orcid":false,"given":"Maria Francesca","family":"Armentano","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University of Basilicata, Via dell\u2019Ateneo Lucano 10, 85100 Potenza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5874-1237","authenticated-orcid":false,"given":"Luigi","family":"Milella","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University of Basilicata, Via dell\u2019Ateneo Lucano 10, 85100 Potenza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"ref_1","first-page":"32","article-title":"Bioaccessibility of polyphenols from hazelnut skin and their use in noodle formulation","volume":"15","author":"Erol","year":"2022","journal-title":"Intern. 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