{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T21:31:19Z","timestamp":1782941479974,"version":"3.54.5"},"reference-count":35,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,12]],"date-time":"2025-04-12T00:00:00Z","timestamp":1744416000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Youth Fund of the National Natural Science Foundation of China","award":["81904067"],"award-info":[{"award-number":["81904067"]}]},{"name":"Youth Fund of the National Natural Science Foundation of China","award":["81904067"],"award-info":[{"award-number":["81904067"]}]},{"name":"Youth Fund of the National Natural Science Foundation of China","award":["81904067"],"award-info":[{"award-number":["81904067"]}]},{"name":"Youth Fund of the National Natural Science Foundation of China","award":["81904067"],"award-info":[{"award-number":["81904067"]}]},{"name":"National Administration of Traditional Chinese Medicine 2021 Qihuang Scholar Support Project (National TCM Education Letter 2022 No. 6)","award":["81904067"],"award-info":[{"award-number":["81904067"]}]},{"name":"National Administration of Traditional Chinese Medicine 2021 Qihuang Scholar Support Project (National TCM Education Letter 2022 No. 6)","award":["81904067"],"award-info":[{"award-number":["81904067"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In the context of osteoporosis closely linked to bone metabolism imbalance caused by estrogen deficiency, total flavonoids of Rhizoma Drynariae (TFRD) exhibit potential anti-osteoporotic activity, yet their multicomponent synergistic mechanism and association with the PI3K\/AKT signaling pathway remain unclear. This study aimed to systematically elucidate the molecular mechanisms by which TFRD regulate bone metabolism and improve osteoporosis in ovariectomized (OVX) rats through the PI3K\/AKT pathway, integrating network pharmacological predictions with animal experimental validation. Methods involved identifying TFRD\u2019s active components using UPLC\/MS-MS, predicting targets with SwissTargetPrediction, constructing a \u201ccomponent-target-disease\u201d network, and performing GO\/KEGG enrichment analysis with MetaScape (v3.5). In vivo experiments established an OVX rat model, randomized into sham, OVX, low-\/high-dose TFRD, and sim groups, assessing bone mineral density (BMD) and mandibular Micro-CT parameters after 12 weeks. Western blot analyzed PI3K, p-AKT1, and related protein expressions. Results showed the high-dose TFRD group significantly increased BMD, improved trabecular bone quantity and structure, and upregulated PI3K, p-PI3K, and p-AKT1 protein expressions compared to the OVX group. Molecular docking confirmed stable binding energy between core components and PI3K\/AKT targets. TFRD may ameliorate estrogen deficiency-induced osteoporosis by activating the PI3K\/AKT signaling pathway, inhibiting bone resorption, and promoting osteogenic differentiation, providing pharmacological evidence for multitarget treatment of osteoporosis with traditional Chinese medicine.<\/jats:p>","DOI":"10.3390\/ijms26083650","type":"journal-article","created":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T06:18:36Z","timestamp":1744611516000},"page":"3650","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Mechanistic Integration of Network Pharmacology and In Vivo Validation: TFRD Combat Osteoporosis via PI3K\/AKT Pathway Activation"],"prefix":"10.3390","volume":"26","author":[{"given":"Chang","family":"Tan","sequence":"first","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7214-3233","authenticated-orcid":false,"given":"Shibo","family":"Cong","sequence":"additional","affiliation":[{"name":"Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanming","family":"Xie","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingjie","family":"Zhi","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"ITC1","DOI":"10.7326\/AITC202401160","article-title":"Osteoporosis","volume":"177","author":"Ensrud","year":"2024","journal-title":"Ann. 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