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This study investigates the therapeutic potential of Periplaneta americana L. extract (PAE) and its molecular mechanisms, integrating network pharmacology and experimental validation. Liquid chromatography\u2013mass spectrometry identified 1355 compounds in PAE. Network pharmacology analysis revealed that inosine, vidarabine, and adenosine 5\u2032-monophosphate (AMP) were core components and the core components synergistically regulated key targets and acted on inflammation-related pathways, thereby establishing a multi-target anti-inflammatory regulatory network. In vivo experiments demonstrated that these compounds significantly alleviated colitis symptoms in dextran sulfate sodium-induced mice, as evidenced by reduced disease activity index scores, preserved colonic mucosal architecture, and decreased inflammatory infiltration. Mechanistically, core compounds down-regulated granulocyte-macrophage colony-stimulating factor (GM-CSF), inducible nitric oxide synthase (iNOS)\/NOS2, monocyte chemoattractant protein 1 (MCP-1), and transforming growth factor beta 1 (TGF-\u03b21), while they up-regulated interleukin-10 (IL-10) and epidermal growth factor (EGF). Additionally, they activated epidermal growth factor receptor (EGFR)-mediated pathways. Molecular docking analysis revealed that adenosine analogs preferentially bound to A1\/A2a receptors, triggering signaling cascades essential for epithelial repair and inflammation resolution. This study established the multi-component, multi-pathway mechanism of PAE in UC, highlighting its dual role in suppressing inflammation and promoting mucosal healing. By bridging traditional herbal use with modern molecular insights, these findings provided a translational foundation for developing PAE-based therapies for UC.<\/jats:p>","DOI":"10.3390\/ijms26125446","type":"journal-article","created":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T09:02:03Z","timestamp":1749200523000},"page":"5446","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Inosine, AMP, and Vidarabine: Network Pharmacology and LC-MS Reveal Key Bioactive Compounds in Periplaneta americana for Ulcerative Colitis Management"],"prefix":"10.3390","volume":"26","author":[{"given":"Yue","family":"Li","sequence":"first","affiliation":[{"name":"School of Artificial Intelligence and Information Technology, Nanjing University of Chinese Medicine, Nanjing 210023, China"},{"name":"Institute of Literature in Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng-Mei","family":"Shi","sequence":"additional","affiliation":[{"name":"Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali 671000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"He","sequence":"additional","affiliation":[{"name":"Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali 671000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zu-Wei","family":"Xi","sequence":"additional","affiliation":[{"name":"Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali 671000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5602-0268","authenticated-orcid":false,"given":"Yi-Hao","family":"Che","sequence":"additional","affiliation":[{"name":"Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali 671000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-Rong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali 671000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Gui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali 671000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Liu","sequence":"additional","affiliation":[{"name":"Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali 671000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kong-Fa","family":"Hu","sequence":"additional","affiliation":[{"name":"School of Artificial Intelligence and Information Technology, Nanjing University of Chinese Medicine, Nanjing 210023, China"},{"name":"Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, Nanjing 210023, China"},{"name":"Jiangsu Research Center for Major Health Risk Management and TCM Control Policy, Nanjing University of Chinese Medicine, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.1016\/S0140-6736(16)32126-2","article-title":"Ulcerative colitis","volume":"389","author":"Ungaro","year":"2017","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/s41572-020-0205-x","article-title":"Ulcerative colitis","volume":"6","author":"Kobayashi","year":"2020","journal-title":"Nat. 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