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Subsequent GO and KEGG enrichment analyses revealed that these targets are primarily involved in biological processes such as the positive regulation of protein kinase B signaling, cellular response to lipopolysaccharide, and inflammatory responses, with significant enrichment in key pathways like the PI3K-Akt signaling pathway. Molecular docking results indicated that podophyllotoxin has strong binding activity with several targets related to inflammation and signal transduction. Animal experiments further validated the significant therapeutic effects of podophyllotoxin in the DSS-induced ulcerative colitis mouse model. Particularly at high doses, podophyllotoxin effectively alleviated ulcerative colitis symptoms, reduced pathological damage to colonic tissues, and enhanced intestinal barrier function. Additionally, podophyllotoxin significantly lowered the levels of inflammatory cytokines (TNF-\u03b1, IL-1\u03b2, IL-6) in the serum and colonic tissues of ulcerative colitis model mice and improved oxidative stress status. More importantly, podophyllotoxin effectively restored the impaired intestinal mucosal barrier function by enhancing the expression of tight junction proteins such as ZO-1 and occludin. Finally, the study revealed that podophyllotoxin may alleviate ulcerative colitis symptoms and promote colonic tissue repair by activating the PI3K\/AKT signaling pathway. These findings provide strong experimental evidence for the potential use of podophyllotoxin as a therapeutic agent for ulcerative colitis and offer valuable insights for the future development of ulcerative colitis treatment strategies targeting the PI3K\/AKT pathway.<\/jats:p>","DOI":"10.33549\/physiolres.935487","type":"journal-article","created":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T09:43:53Z","timestamp":1747734233000},"page":"287-300","source":"Crossref","is-referenced-by-count":3,"title":["Podophyllotoxin Alleviates DSS-Induced Ulcerative Colitis via PI3K\/AKT Pathway Activation"],"prefix":"10.33549","author":[{"given":"T","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Emergency, The Affiliated Hospital of Southwest Medical University. 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International Immunopharmacology. 2020;85:106661. https:\/\/doi.org\/10.1016\/j.intimp.2020.106661","DOI":"10.1016\/j.intimp.2020.106661"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"Tatiya-Aphiradee N, Chatuphonprasert W, Jarukamjorn K. Immune response and inflammatory pathway of ulcerative colitis. Journal of basic and clinical physiology and pharmacology. 2018;30(1):1-10. https:\/\/doi.org\/10.1515\/jbcpp-2018-0036","DOI":"10.1515\/jbcpp-2018-0036"},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"Nakase H, Sato N, Mizuno N, Ikawa Y. The influence of cytokines on the complex pathology of ulcerative colitis. Autoimmunity reviews. 2022;21(3):103017. https:\/\/doi.org\/10.1016\/j.autrev.2021.103017","DOI":"10.1016\/j.autrev.2021.103017"},{"key":"ref33","doi-asserted-by":"publisher","unstructured":"Farr\u00e9 R, Fiorani M, Abdu Rahiman S, Matteoli G. Intestinal permeability, inflammation and the role of nutrients. Nutrients. 2020;12(4):1185. https:\/\/doi.org\/10.3390\/nu12041185","DOI":"10.3390\/nu12041185"},{"key":"ref34","doi-asserted-by":"publisher","unstructured":"Barbara G, Barbaro MR, Fuschi D, Palombo M, Falangone F, Cremon C, Marasco G, Stanghellini V. Inflammatory and microbiota-related regulation of the intestinal epithelial barrier. Frontiers in nutrition. 2021;8:718356. https:\/\/doi.org\/10.3389\/fnut.2021.718356 https:\/\/doi.org\/10.3389\/fnut.2021.790387","DOI":"10.3389\/fnut.2021.718356"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"Wan Y, Yang L, Jiang S, Qian D, Duan J. Excessive apoptosis in ulcerative colitis: crosstalk between apoptosis, ROS, ER stress, and intestinal homeostasis. Inflammatory bowel diseases. 2022;28(4):639-48. https:\/\/doi.org\/10.1093\/ibd\/izab277","DOI":"10.1093\/ibd\/izab277"},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"Alzoghaibi MA, Al Mofleh IA, Al-Jebreen AM. Lipid peroxides in patients with inflammatory bowel disease. Saudi Journal of Gastroenterology. 2007;13(4):187-90. https:\/\/doi.org\/10.4103\/1319-3767.36750","DOI":"10.4103\/1319-3767.36750"},{"key":"ref37","doi-asserted-by":"publisher","unstructured":"Ghulam Mohyuddin S, Khan I, Zada A, Qamar A, Arbab AAI, Ma X-b, Yu Z-c, Liu X-X, Yong Y-H, Ju XH. Influence of heat stress on intestinal epithelial barrier function, tight junction protein, and immune and reproductive physiology. BioMed Research International. 2022;2022(1):8547379. https:\/\/doi.org\/10.1155\/2022\/8547379","DOI":"10.1155\/2022\/8547379"},{"key":"ref38","doi-asserted-by":"publisher","unstructured":"Alzoghaibi MA, Al-Mofleh IA, Al-Jebreen AM. Antioxidant activities for superoxide dismutase in patients with Crohn's disease. Journal of Basic and Clinical Physiology and Pharmacology. 2014;25(1):59-62. https:\/\/doi.org\/10.1515\/jbcpp-2013-0042","DOI":"10.1515\/jbcpp-2013-0042"},{"key":"ref39","doi-asserted-by":"publisher","unstructured":"Vaidya FU, Chhipa AS, Sagar N, Pathak C. Oxidative stress and inflammation can fuel cancer. Role of oxidative stress in pathophysiology of diseases. 2020:229-58. https:\/\/doi.org\/10.1007\/978-981-15-1568-2_14","DOI":"10.1007\/978-981-15-1568-2_14"},{"key":"ref40","doi-asserted-by":"publisher","unstructured":"Zhu L, Shen H, Gu P-Q, Liu Y-J, Zhang L, Cheng J-F. Baicalin alleviates TNBS-induced colitis by inhibiting PI3K\/AKT pathway activation. Experimental and therapeutic medicine. 2020;20(1):581-90. https:\/\/doi.org\/10.3892\/etm.2020.8718","DOI":"10.3892\/etm.2020.8718"},{"key":"ref41","doi-asserted-by":"publisher","unstructured":"Li C, Wang L, Zhao J, Wei Y, Zhai S, Tan M, Guan K, Huang Z, Chen C. Lonicera rupicola Hook. f. et Thoms flavonoids ameliorated dysregulated inflammatory responses, intestinal barrier, and gut microbiome in ulcerative colitis via PI3K\/AKT pathway. Phytomedicine. 2022;104:154284. https:\/\/doi.org\/10.1016\/j.phymed.2022.154284","DOI":"10.1016\/j.phymed.2022.154284"},{"key":"ref42","doi-asserted-by":"publisher","unstructured":"Acosta-Martinez M, Cabail MZ. The PI3K\/Akt pathway in meta-inflammation. 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