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Natural conjugated taurocholic acid (TCA) possesses anti-inflammatory properties and shows potential therapeutic effects against UC, although the underlying mechanisms remain unclear. Methods: This study employed an integrative approach\u2014combining network pharmacology, bioinformatics, machine learning, immune infiltration analysis, and molecular docking\u2014to investigate the therapeutic mechanisms of TCA in UC. UC-related gene expression datasets were obtained from the Gene Expression Omnibus (GEO) database, and potential TCA targets were predicted using the Comparative Toxicogenomics Database (CTD) and TargetNet platforms. Differentially expressed genes (DEGs) were identified and analyzed via GO and KEGG enrichment analyses. Results: Four machine learning algorithms (XGBoost, RF, SVM, and NNet) were used to identify six hub genes (TGM2, MMP9, ABCB1, NOS2, ABCG2, CASP1), which were further validated using an artificial neural network. Immune infiltration analysis with CIBERSORT revealed significant alterations in immune cell populations in UC tissues. Further validation through an artificial neural network model confirmed their predictive ability. The enrichment analysis of the hub genes highlighted their roles in immune-related pathways, while the immune infiltration analysis indicated significant differences in immune cell populations between ulcerative colitis tissues and control tissues. The molecular docking results showed that the binding energies of these six proteins to TCA were lower than \u22125 kcal\/mol, with TGM2 having the strongest binding affinity (\u221210 kcal\/mol). The intervention of TCA on colitis mice could improve the inflammatory response by regulating the expression of the TGM2 gene. Conclusions: In conclusion, this study suggests that taurocholate alleviates ulcerative colitis by targeting key genes such as TGM2 and modulating immune-related pathways, providing a novel basis for future therapeutic exploration.<\/jats:p>","DOI":"10.3390\/genes16091024","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T12:25:57Z","timestamp":1756470357000},"page":"1024","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrating Transcriptomics, Network Pharmacology, and Machine Learning to Reveal Transglutaminase 2 (TGM2) as a Key Target Mediating Taurocholate Efficacy in Colitis"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-6431-6330","authenticated-orcid":false,"given":"Junhong","family":"Zhu","sequence":"first","affiliation":[{"name":"Yunnan Provincial Key Laboratory of Animal Nutrition and Feed, Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huijin","family":"Jia","sequence":"additional","affiliation":[{"name":"Yunnan Provincial Key Laboratory of Animal Nutrition and Feed, Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lanlan","family":"Yi","sequence":"additional","affiliation":[{"name":"Yunnan Provincial Key Laboratory of Animal Nutrition and Feed, Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guangyao","family":"Song","sequence":"additional","affiliation":[{"name":"Yunnan Provincial Key Laboratory of Animal Nutrition and Feed, Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pengfei","family":"Fu","sequence":"additional","affiliation":[{"name":"Yunnan Provincial Key Laboratory of Animal Nutrition and Feed, Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9961-821X","authenticated-orcid":false,"given":"Wenjie","family":"Cheng","sequence":"additional","affiliation":[{"name":"Yunnan Provincial Key Laboratory of Animal Nutrition and Feed, Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuxiao","family":"Xie","sequence":"additional","affiliation":[{"name":"Yunnan Provincial Key Laboratory of Animal Nutrition and Feed, Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China"},{"name":"College of Biology and Agriculture, Zunyi Normal University, Zunyi 563006, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenzhe","family":"Shi","sequence":"additional","affiliation":[{"name":"Yunnan Provincial Key Laboratory of Animal Nutrition and Feed, Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sumei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Yunnan Provincial Key Laboratory of Animal Nutrition and Feed, Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"675","DOI":"10.14309\/ajg.0000000000003143","article-title":"Disproportionately Increasing Incidence of Inflammatory Bowel Disease in Females and the Elderly: An Update Analysis from the Global Burden of Disease Study 2021","volume":"120","author":"Danpanichkul","year":"2024","journal-title":"Am. 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