{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T20:19:15Z","timestamp":1788812355837,"version":"build-2803163510"},"reference-count":37,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,14]],"date-time":"2022-09-14T00:00:00Z","timestamp":1663113600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health 5xMille 2021 and 2022"},{"name":"Fondazione Veronesi"},{"name":"AISF Associazione Italiana per lo Studio del Fegato"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Non-alcoholic fatty liver disease (NAFLD)-related liver fibrosis results in the encapsulation of injured liver parenchyma by a collagenous scar mainly imputable to hepatic stellate cells\u2019 activation. Approved pharmacological treatments against NAFLD-related fibrosis are still lacking, but natural compounds such as hydroxytyrosol (HXT) and vitamin E (VitE), are emerging as promising therapeutic opportunities. In this study, the potential anti-fibrotic effect of HXT + VitE combination therapy was investigated in vitro and in vivo. In particular, tumor growth factor (TGF)-\u03b2-activated LX-2 cells as an in vitro model, and carbon tetrachloride plus a Western diet as a mice model were employed. The effect of HXT + VitE on fibrosis was also investigated in children with biopsy-proven NAFLD. Our results demonstrated that HXT + VitE caused a reduction of proliferation, migration, contractility, and expression of pro-fibrogenic genes in TGF-\u03b2-activated LX-2 cells. HXT + VitE treatment also antagonized TGF-\u03b2-dependent upregulation of pro-oxidant NOX2 by interfering with nuclear translocation\/activation of SMAD2\/3 transcription factors. The mouse model of NAFLD-related fibrosis treated with HXT + VitE showed a marked reduction of fibrosis pattern by histology and gene expression. Accordingly, in children with NAFLD, HXT + VitE treatment caused a decrease of circulating levels of PIIINP and NOX2 that was supported over time. Our study suggests that HXT + VitE supplementation may improve NAFLD-related fibrosis.<\/jats:p>","DOI":"10.3390\/nu14183791","type":"journal-article","created":{"date-parts":[[2022,9,14]],"date-time":"2022-09-14T23:16:36Z","timestamp":1663197396000},"page":"3791","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Combination Treatment with Hydroxytyrosol and Vitamin E Improves NAFLD-Related Fibrosis"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5365-3123","authenticated-orcid":false,"given":"Nadia","family":"Panera","sequence":"first","affiliation":[{"name":"Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Rita","family":"Braghini","sequence":"additional","affiliation":[{"name":"Research Unit of Molecular Genetics of Complex 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