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Melatonin is a well\u2010recognized antioxidant and an anti\u2010inflammatory agent that benefits multiple organs. However, the beneficial effects of melatonin on gut leakiness\u2013associated liver fibrosis have not been systemically studied. Here, we investigated the protective mechanisms of melatonin against thioacetamide (TAA)\u2013induced gut barrier dysfunction and hepatic fibrosis by focusing on posttranslational protein modifications through the gut\u2013liver axis. Our results showed that gut leakiness markers, including decreased gut tight\/adherens junction proteins (TJ\/AJs) with increased intestinal deformation, apoptosis, and serum endotoxin, were observed early at 1 week after TAA exposure. Liver injury, apoptosis, and fibrosis were prominent at 2 and 4 weeks. Mechanistically, we found that gut TJ\/AJs were hyper\u2010acetylated, followed by ubiquitin\u2010dependent proteolysis, leading to their degradation and gut leakiness. Gut dysbiosis, hepatic protein hyper\u2010acetylation, and SIRT1 downregulation were also observed. Consistently, intestinal <jats:italic>Sirt1<\/jats:italic> deficiency greatly enhanced protein hyper\u2010acetylation, gut leakiness, endotoxemia, and liver fibrosis. Pretreatment with melatonin prevented or improved all these changes in both the gut and liver. Furthermore, melatonin blunted protein acetylation and injury in TAA\u2013exposed T84 human intestinal and AML12 mouse liver cells. Overall, this study demonstrated novel mechanisms by which melatonin prevents gut leakiness and liver fibrosis through the gut\u2013liver axis by attenuating the acetylation of intestinal and hepatic proteins. Thus, melatonin consumption can become a potentially safe supplement for liver fibrosis patients by preventing protein hyper\u2010acetylation and gut leakiness.<\/jats:p>","DOI":"10.1111\/jpi.13007","type":"journal-article","created":{"date-parts":[[2024,9,13]],"date-time":"2024-09-13T14:38:32Z","timestamp":1726238312000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Melatonin Prevents Thioacetamide\u2013Induced Gut Leakiness and Liver Fibrosis Through the Gut\u2013Liver Axis via Modulating Sirt1\u2010Related Deacetylation of Gut Junctional Complex and Hepatic Proteins"],"prefix":"10.1111","volume":"76","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9334-0984","authenticated-orcid":false,"given":"Wiramon","family":"Rungratanawanich","sequence":"first","affiliation":[{"name":"Section of Molecular Pharmacology and Toxicology National Institute on Alcohol Abuse and Alcoholism Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4084-3082","authenticated-orcid":false,"given":"Karli Rae","family":"LeFort","sequence":"additional","affiliation":[{"name":"Section of Molecular Pharmacology and Toxicology National Institute on Alcohol Abuse and Alcoholism Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9864-0265","authenticated-orcid":false,"given":"Young\u2010Eun","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Food and Nutrition Andong National University Andong Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5920-7784","authenticated-orcid":false,"given":"Xiaoling","family":"Li","sequence":"additional","affiliation":[{"name":"Signal Transduction Laboratory National Institute of Environmental Health Sciences Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3954-3497","authenticated-orcid":false,"given":"Byoung\u2010Joon","family":"Song","sequence":"additional","affiliation":[{"name":"Section of Molecular Pharmacology and Toxicology National Institute on Alcohol Abuse and Alcoholism Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,9,13]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1300575"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2019.07.060"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32285"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2016-312729"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.04.033"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxac030"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2019-318427"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2024.2331460"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30652"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.02.005"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-079X.1996.tb00294.x"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21197174"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox13040439"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1339304"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(03)00504-X"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/biolre\/ioae087"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40261-015-0368-5"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1210\/jcem-61-6-1214"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00002.2015"},{"key":"e_1_2_10_21_1","first-page":"23","article-title":"Role of Melatonin in Upper Gastrointestinal Tract","volume":"58","author":"Konturek S. 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