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This study aimed to identify RH\u2019s bioactive fractions, elucidate protection mechanisms, establish flavonoid dose-effect relationships, and determine the pharmacodynamic basis. Methods: Chemical profiling quantified eight flavonoids via HPLC. Network pharmacology screened targets\/pathways using TCMSP, GeneCards databases. In vivo validation employed cisplatin\u2013induced injury models in Wistar rats (n = 10\/group). Assessments included: behavioral monitoring; organ indices; ELISA (MTL, VIP, IFN\u2013\u03b3, IgG, IL\u20136, TNF\u2013\u03b1 etc.); H&amp;E; and Western blot:(SCF, c\u2013Kit, p65). Dose\u2013effect correlations were analyzed by PLS\u2013DA. Results: Content determination indicated that Calycosin\u20137\u2013glucoside and Ononin were notably enriched on both the n\u2013BuOH part and the EtOAc part. Network pharmacology identified 5 core flavonoids and 8 targets enriched in IL\u201317\/TNF signaling pathways. n\u2013BuOH treatment minimized weight loss vs. MCG, increased spleen\/thymus indices. n\u2013BuOH and HPS normalized gastrointestinal, immune, inflammatory biomarkers (p &lt; 0.01 vs. MCG). Histopathology confirmed superior mucosal protection in n\u2013BuOH group vs. MCG. Western blot revealed n\u2013BuOH significantly downregulated SCF, c\u2013kit, and p65 expressions in both gastric and intestinal tissues (p &lt; 0.001 vs. MCG). PLS\u2013DA demonstrated Calycosin\u20137\u2013glucoside had the strongest dose\u2013effect correlation (VIP &gt; 1) with protective outcomes. Conclusions: The n\u2013BuOH fraction of RH is the primary bioactive component against chemotherapy\u2013induced gastrointestinal injury, with Calycosin\u20137\u2013glucoside as its key effector. Protection is mediated through SCF\/c\u2013Kit\/NF\u2013\u03baB pathway inhibition, demonstrating significant dose\u2013dependent efficacy. These findings support RH\u2019s potential as a complementary therapy during chemotherapy.<\/jats:p>","DOI":"10.3390\/ph18071072","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T07:56:14Z","timestamp":1753084574000},"page":"1072","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Study on the Mechanism and Dose\u2013Effect Relationship of Flavonoids in Different Extracts of Radix Hedysari Against Gastrointestinal Injury Induced by Chemotherapy"],"prefix":"10.3390","volume":"18","author":[{"given":"Shasha","family":"Zhao","sequence":"first","affiliation":[{"name":"College of Pharmacy, Gansu University of Traditional Chinese Medicine, Lanzhou 730000, China"},{"name":"State Administration of Traditional Chinese Medicine Class III Laboratory (Key Laboratory of Traditional Chinese Medicine Chemistry), Lanzhou 730000, China"},{"name":"Northwest China\u2013Tibet Medicine Collaborative Innovation Center, Lanzhou 730000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miaomiao","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Gansu University of Traditional Chinese Medicine, Lanzhou 730000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zimu","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Gansu University of Traditional Chinese Medicine, Lanzhou 730000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hai","family":"He","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Gansu University of Traditional Chinese Medicine, Lanzhou 730000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziyang","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Gansu University of Traditional Chinese Medicine, Lanzhou 730000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyu","family":"Zhu","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Gansu University of Traditional Chinese Medicine, Lanzhou 730000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhijia","family":"Cui","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Gansu University of Traditional Chinese Medicine, Lanzhou 730000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Shao","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Gansu University of Traditional Chinese Medicine, Lanzhou 730000, China"},{"name":"State Administration of Traditional Chinese Medicine Class III Laboratory (Key Laboratory of Traditional Chinese Medicine Chemistry), Lanzhou 730000, China"},{"name":"Northwest China\u2013Tibet Medicine Collaborative Innovation Center, Lanzhou 730000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2551","DOI":"10.1007\/s00210-023-02781-2","article-title":"Effects of Chemotherapy on the Immune System: Implications for Cancer Treatment and Patient Outcomes","volume":"397","author":"Sharma","year":"2024","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. 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