{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T12:00:27Z","timestamp":1791460827318,"version":"4.3.4"},"reference-count":44,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,6,21]],"date-time":"2025-06-21T00:00:00Z","timestamp":1750464000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian ministry of health: Ricerca Corrente 2025"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Non-alcoholic fatty liver disease (NAFLD) is characterized by an accumulation of fat in hepatocytes, and it may progress, under additional triggering factors, to non-alcoholic steatohepatitis (NASH). Effective strategies to counteract this progression are essential, especially considering that at the moment, there is a lack of approved pharmacological therapies. Our previous study showed that the daily consumption of Navelina oranges significantly reduced hepatic steatosis in patients with Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD). Starting with our previous study, here, we have investigated the molecular targets through which Hesperidin (HE), a citrus flavanone, is able to prevent the progression of NAFLD to NASH using an in vitro model. In Hepa-RG cells exposed to NAFLD Promoting Agents, HE reduced lipid droplet accumulation (~35%) and suppressed de novo lipogenesis, with decreased expression of FASN (0.62 \u00b1 0.06 vs. 0.39 \u00b1 0.03 at 100 \u00b5g\/mL) and SCD1 (0.05 \u00b1 0.001 vs. 0.03 \u00b1 0.004 at 50 \u00b5g\/mL). HE also enhanced fatty acid oxidation by increasing SIRT1 (0.73 \u00b1 0.16 vs. 2.36 \u00b1 0.10 at 50 \u00b5g\/mL) and PGC1\u03b1 (0.71 \u00b1 0.03 vs. 0.89 \u00b1 0.003 at 50 \u00b5g\/mL). In LX-2 cells, HE downregulated COL1A1 (1.48 \u00b1 0.10 vs. 0.90 \u00b1 0.11 at 100 \u00b5g\/mL) and \u03b1-SMA (1.21 \u00b1 0.16 vs. 0.76 \u00b1 0.07 at 75 \u00b5g\/mL) and upregulated MMP3 (0.64 \u00b1 0.05 vs. 0.98 \u00b1 0.07) and MMP9 (0.99 \u00b1 0.005 vs. 2.61 \u00b1 0.16 at 100 \u00b5g\/mL). In conclusion, HE may offer a promising approach for NAFLD\/NASH prevention and treatment, demonstrating in vitro its potential to reduce hepatic steatosis and fibrosis.<\/jats:p>","DOI":"10.3390\/ijms26135982","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T09:08:44Z","timestamp":1750669724000},"page":"5982","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Hesperidin Is a Promising Nutraceutical Compound in Counteracting the Progression of NAFLD In Vitro"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8946-7832","authenticated-orcid":false,"given":"Miriam","family":"Cofano","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\/0009-0008-5909-057X","authenticated-orcid":false,"given":"Ilenia","family":"Saponara","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"}]},{"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"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1038\/nrgastro.2013.171","article-title":"The Global NAFLD Epidemic","volume":"10","author":"Loomba","year":"2013","journal-title":"Nat. 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