{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T12:01:16Z","timestamp":1791460876959,"version":"4.3.4"},"reference-count":42,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T00:00:00Z","timestamp":1767744000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Italian ministry of health","doi-asserted-by":"crossref","award":["Ricerca Corrente 2025 (DDG. 851\/15)"],"award-info":[{"award-number":["Ricerca Corrente 2025 (DDG. 851\/15)"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Liver fibrosis is characterized by an excessive accumulation of extracellular matrix (ECM) proteins as a wound-healing response to chronic liver injury, leading to tissue scarring and organ dysfunction. Natural compounds, including phytonutrients and polyphenols, have been shown to exert protective effects by reducing profibrotic biomarkers in vitro and in vivo models. Here, we provide the first evidence that the polyphenol hesperidin (HE) can counteract the onset of fibrotic responses in an ex vivo mouse liver fibrosis model induced by Transforming Growth Factor-\u03b21 (TGF-\u03b21) (5 ng\/mL). Notably, HE drives early ECM remodeling in the fibrotic mouse liver tissue. Fibrosis-related parameters were assessed at both the transcriptional and translational levels after treatment with HE at increasing concentrations of 50, 75, and 100 \u00b5g\/mL. Interestingly, HE at 75 \u00b5g\/mL exerted the strongest beneficial effect, significantly decreasing the gene expression of \u03b1-SMA, SERPINH-1, FN-1, VIM and COL1A1 and counteracting the TGF-\u03b21-induced upregulation of key fibrotic markers, including \u03b1-SMA, COL1A2, and VIM, reflecting its capacity to attenuate myofibroblast activation and ECM production and modulating membrane lipid peroxidation. Furthermore, HE inhibited SMAD2 phosphorylation, suggesting that its antifibrotic activity may involve the modulation of the TGF-\u03b2\/SMAD signaling pathway. Moreover, it promoted an anti-inflammatory response, due to a decrease in IL-1\u03b2 and IL-6 expression. Our study highlights the potential of the ex vivo model as a platform for evaluating the antifibrotic efficacy of natural molecules, and it suggests significant translational implications and new opportunities for developing innovative therapeutic strategies.<\/jats:p>","DOI":"10.3390\/ijms27020594","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T08:26:56Z","timestamp":1767774416000},"page":"594","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Anti-Fibrotic and Anti-Inflammatory Effects of Hesperidin in an Ex Vivo Mouse Model of Early-Onset Liver Fibrosis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5909-057X","authenticated-orcid":false,"given":"Ilenia","family":"Saponara","sequence":"first","affiliation":[{"name":"Laboratory of Nutritional Biochemistry, National Institute of Gastroenterology IRCCS \u201cSaverio de Bellis\u201d, 70013 Castellana Grotte, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8946-7832","authenticated-orcid":false,"given":"Miriam","family":"Cofano","sequence":"additional","affiliation":[{"name":"Laboratory of Nutritional Biochemistry, National Institute of Gastroenterology IRCCS \u201cSaverio de Bellis\u201d, 70013 Castellana Grotte, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7912-9023","authenticated-orcid":false,"given":"Valentina","family":"De Nunzio","sequence":"additional","affiliation":[{"name":"Laboratory of Nutritional Biochemistry, National Institute of Gastroenterology IRCCS \u201cSaverio de Bellis\u201d, 70013 Castellana Grotte, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giusy","family":"Bianco","sequence":"additional","affiliation":[{"name":"Animal Facility, National Institute of Gastroenterology IRCCS \u201cSaverio de Bellis\u201d, 70013 Castellana Grotte, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1661-5504","authenticated-orcid":false,"given":"Raffaele","family":"Armentano","sequence":"additional","affiliation":[{"name":"Histopathology Unit, National Institute of Gastroenterology IRCCS \u201cSaverio de Bellis\u201d, 70013 Castellana Grotte, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9042-7082","authenticated-orcid":false,"given":"Giuliano","family":"Pinto","sequence":"additional","affiliation":[{"name":"Laboratory of Nutritional Biochemistry, National Institute of Gastroenterology IRCCS \u201cSaverio de Bellis\u201d, 70013 Castellana Grotte, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2969-5052","authenticated-orcid":false,"given":"Emanuela","family":"Aloisio Caruso","sequence":"additional","affiliation":[{"name":"Laboratory of Nutritional Biochemistry, National Institute of Gastroenterology IRCCS \u201cSaverio de Bellis\u201d, 70013 Castellana Grotte, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1218-599X","authenticated-orcid":false,"given":"Matteo","family":"Centonze","sequence":"additional","affiliation":[{"name":"Laboratory of Nutritional Biochemistry, National Institute of Gastroenterology IRCCS \u201cSaverio de Bellis\u201d, 70013 Castellana Grotte, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2274-2198","authenticated-orcid":false,"given":"Maria","family":"Notarnicola","sequence":"additional","affiliation":[{"name":"Laboratory of Nutritional Biochemistry, National Institute of Gastroenterology IRCCS \u201cSaverio de Bellis\u201d, 70013 Castellana Grotte, Italy"},{"name":"Unit of Clinical Pathology, National Institute of Gastroenterology IRCCS \u201cSaverio de Bellis\u201d, 70013 Castellana Grotte, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1172\/JCI88881","article-title":"Liver Inflammation and Fibrosis","volume":"127","author":"Koyama","year":"2017","journal-title":"J. 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