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This study investigated the hepatoprotective and antioxidative effects of mangosteen pericarp extract (MPE) in an experimental model of diquat-induced oxidative stress in laying hens. A total of 270 Hy-Line White laying hens were randomly assigned to three groups: control group (CON), diquat-challenged group (DQ), and MEP intervention with diquat-challenged group (MQ), with six replicates of 15 birds each. The results showed that MPE supplementation effectively mitigated the hepatic oxidative damage caused by diquat, as evidenced by the increased ALT and AST activity, improved lipid metabolism, and reduced hepatic fibrosis. Mechanistically, MPE activated the NRF2\/HO-1 antioxidant pathway, thus enhancing the liver\u2019s ability to counteract ROS-induced damage and reducing lipid droplet accumulation in liver tissue. MPE supplementation restored intestinal barrier integrity by upregulating tight junction protein expression (Occludin-1 and ZO-1), enhancing MUC-2 expression, and thereby decreasing gut microbiota-derived LPS transferring from the intestine. Additionally, MPE also modulated gut microbiota composition by enriching beneficial bacterial genera such as Lactobacillus and Ruminococcus while suppressing the growth of potentially harmful taxa (e.g., Bacteroidales and UCG-010). Fecal microbiota transplantation (FMT) from MPE-treated donors into diquat-exposed recipients reproduced these beneficial effects, further highlighting the role of gut microbiota modulation in mediating MPE\u2019s systemic protective actions. Together, these findings demonstrated that MPE alleviated DQ-induced liver injury and oxidative stress through a combination of antioxidant activity, protection of intestinal barrier function, and modulation of gut microbiota, positioning MPE as a promising natural strategy for mitigating oxidative stress-related liver damage by regulating the gut microbiota and gut\u2013liver axis in poultry.<\/jats:p>","DOI":"10.3390\/antiox14091045","type":"journal-article","created":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T06:25:57Z","timestamp":1756189557000},"page":"1045","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Mangosteen Pericarp Extract Mitigates Diquat-Induced Hepatic Oxidative Stress by NRF2\/HO-1 Activation, Intestinal Barrier Integrity Restoration, and Gut Microbiota Modulation"],"prefix":"10.3390","volume":"14","author":[{"given":"Weichen","family":"Huang","sequence":"first","affiliation":[{"name":"Zhejiang Key Laboratory of Nutrition and Breeding for High-Quality Animal Products, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China"},{"name":"ZJU-Xinchang Joint Innovation Centre (TianMu Laboratory), Gaochuang Hi-Tech Park, Shaoxing 312500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Lv","sequence":"additional","affiliation":[{"name":"Zhejiang Key Laboratory of Nutrition and Breeding for High-Quality Animal Products, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China"},{"name":"Hainan Institute, Zhejiang University, Sanya 572000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenhao","family":"Zou","sequence":"additional","affiliation":[{"name":"Zhejiang Key Laboratory of Nutrition and Breeding for High-Quality Animal Products, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoyue","family":"Ge","sequence":"additional","affiliation":[{"name":"Zhejiang Key Laboratory of Nutrition and Breeding for High-Quality Animal Products, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China"},{"name":"Hainan Institute, Zhejiang University, Sanya 572000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenao","family":"Zhan","sequence":"additional","affiliation":[{"name":"Zhejiang Key Laboratory of Nutrition and Breeding for High-Quality Animal Products, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Shen","sequence":"additional","affiliation":[{"name":"Zhejiang Key Laboratory of Nutrition and Breeding for High-Quality Animal Products, College of Animal Sciences, Zhejiang University, Hangzhou 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