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This study aims to investigate the potential of Chinese medicinal rhubarb to enhance bowel motility through modulation of calcium ion signaling in the gastrointestinal tract. A multi-omics approach integrating network pharmacology, KEGG pathway enrichment, and protein\u2013protein interaction (PPI) analyses to identify rhubarb\u2019s active components and target genes linked to AP. KEGG analysis highlighted key genes in the calcium ion pathway, facilitating the construction of a network pharmacology framework. C57BL\/6 mice were single-blind randomly given saline or rhubarb gavage (0.2\u00a0mL\/10\u00a0g, thrice daily for 2\u00a0days). Ileum tissues and serum were collected to measure key genes, acetylcholine (ACh), and acetylcholinesterase (AChE). Similarly, mild to moderate AP patients in Pingxiang People\u2019s Hospital were single-blind randomly assigned to control or rhubarb groups, with serum analyzed for AChE levels. Multi-dimensional analyses identified ten active components in rhubarb that interact with 67 target proteins. Cross-referencing with AP-related targets identified 55 key regulatory genes, ten of which were significantly enriched in the calcium signaling pathway. Animal studies demonstrated that rhubarb significantly increased ACh in the mice ileum (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0023) and serum AChE levels (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001). Q-PCR analysis indicated upregulation of nine calcium pathway-related genes. In a randomized single-blind trial with 10 AP patients, those receiving oral rhubarb had significantly more frequent bowel movements (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001) and higher serum AChE levels (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001) than controls. No adverse events occurred. Rhubarb increases diarrhea in mice by enhancing gastrointestinal motility, activating calcium ion signaling, and boosting ACh and AChE release. It also raises serum AChE levels and defecation frequency in AP patients. These effects may explain rhubarb\u2019s therapeutic role in treating gastrointestinal motility disorders linked to AP.\n                  <\/jats:p>\n                  <jats:p>Trial registration number: ITMCTR2025002044.<\/jats:p>","DOI":"10.1038\/s41598-026-39372-z","type":"journal-article","created":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T09:03:18Z","timestamp":1770973398000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Rhubarb enhances gastrointestinal motility via calcium-mediated intestinal acetylcholine release: a network pharmacology study"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0840-0143","authenticated-orcid":false,"given":"Zhiyong","family":"Wen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weihua","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jialing","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Songling","family":"Tan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianbo","family":"Wen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,2,13]]},"reference":[{"key":"39372_CR1","doi-asserted-by":"publisher","unstructured":"Chinese Pancreatic Surgery Association, C. 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