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Current treatments, including anti-inflammatory drugs and biologics, often have limited efficacy and significant side effects, highlighting the need for novel therapeutic approaches. Phellodendrine (PHE) is a characteristic ingredient of Phellodendri chinensis, yet its effects and mechanisms on IBD remain elusive. The present study evaluated the potential of PHE for preventing dextran sulfate sodium-induced IBD in zebrafish. PHE effectively reduced inflammatory cell infiltration and modulated polarized macrophages. The qPCR results further confirmed the down-regulation of pro-inflammatory genes and up-regulation of anti-inflammatory factors. Consequently, PHE promoted the resolution of IBD inflammation. PHE also restored intestinal barrier integrity by enhancing MUC2 expression, increasing goblet cell counts, and reducing intestinal permeability of both chemical and physical barriers. In addition, PHE was associated with alterations in the gut microbiome, including a reduction in potentially pathogenic microbes and an increase in beneficial microbial populations. PHE also alleviated oxidative stress. Network pharmacology suggested the potential involvement of the IL-17 signaling pathway, the lipid and atherosclerosis pathway, and the TNF signaling pathway in the preventive effects of PHE against intestinal inflammation in the zebrafish model. In vivo gene expression analysis suggested that JUN, PTGS2, IL1B, DRD2, CALM1, and HSP90AA1 may serve as putative targets of PHE. Collectively, our results indicate that PHE demonstrates potential anti-inflammatory and barrier-protective activities in a zebrafish model of intestinal inflammation. The pharmacological mechanisms by which PHE restores intestinal barriers (microbial, chemical, physical, and immune barriers) include resolving inflammation, decreasing ROS production, and enhancing lipid accumulation in the lumen overlying the intestinal mucus barrier. This study provides novel insights into the preventive effects of PHE against intestinal inflammation in a zebrafish model, suggesting its potential as a candidate for further investigation.<\/jats:p>","DOI":"10.3390\/biom16081092","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T01:26:23Z","timestamp":1785115583000},"page":"1092","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unraveling Effects and Pharmacological Mechanisms of Phellodendrine on Inflammatory Bowel Disease"],"prefix":"10.3390","volume":"16","author":[{"given":"Yufeng","family":"Xie","sequence":"first","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry, School of Geography and Environmental Engineering, Gannan Normal University, Ganzhou 341000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry, School of Geography and Environmental Engineering, Gannan Normal University, Ganzhou 341000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuqianzi","family":"Wu","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry, School of Geography and Environmental Engineering, Gannan Normal University, Ganzhou 341000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayin","family":"Teng","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry, School of Geography and Environmental Engineering, Gannan Normal University, Ganzhou 341000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaorun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry, School of Geography and Environmental Engineering, Gannan Normal University, Ganzhou 341000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Sun","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry, School of Geography and Environmental Engineering, Gannan Normal University, Ganzhou 341000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixin","family":"Chen","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry, School of Geography and Environmental Engineering, Gannan Normal University, Ganzhou 341000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2259-9830","authenticated-orcid":false,"given":"Lijian","family":"Ding","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Health Science Center, Ningbo University, Ningbo 315211, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Yuan","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry, School of Geography and Environmental Engineering, Gannan Normal University, Ganzhou 341000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1038\/s41575-019-0172-4","article-title":"Macrophages in intestinal inflammation and resolution: A potential therapeutic target in IBD","volume":"16","author":"Na","year":"2019","journal-title":"Nat. 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