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The aim of this study is to investigate whether phillygenin (PHI), an active component of\n                    <jats:italic>Forsythiae Fructus<\/jats:italic>\n                    , promotes osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) by modulating the FAK\/GSK\u20103\u03b2\/\u03b2\u2010catenin signaling axis. Experimental procedure: In\u00a0vivo, an ovariectomized (OVX) mouse model was employed to mimic postmenopausal bone loss. In\u00a0vitro, osteoclastogenesis was evaluated using tartarate\u2010resistant acid phosphatase (TRAP) enzymatic assays, while osteogenic differentiation of BMSCs was assessed through alkaline phosphatase (ALP) and alizarin red S (ARS) staining. Cell proliferation and viability were examined using the CCK\u20108 assay. Osteogenic markers, including ALP, RUNX2, osteopontin (OPN), as well as signaling proteins, such as phosphorylated FAK at\u00a0Y397 (pFAKY397), phosphorylated glycogen synthase kinase\u20103 beta (pGSK\u20103\u03b2), and \u03b2\u2010catenin, were analyzed by western blot and immunofluorescence analyses. Specific inhibitors of the FAK and \u03b2\u2010catenin (Y15 and XAV\u2010939) were employed for mechanistic validation. PHI treatment significantly decreased the number and size of osteoclasts in a dose\u2010dependent way. In OVX mice, PHI preserved trabecular microarchitecture, increased bone mineral density, and inhibited osteoclast formation dose\u2010dependently. Low doses of PHI significantly promoted osteogenic differentiation and mineralization of BMSCs without affecting cell proliferation and viability. Mechanistically, PHI upregulated the expression of pFAKY397, pGSK\u20103\u03b2, and \u03b2\u2010catenin. Inhibition of the pathway, achieved through the use of Y15 and XAV\u2010939, attenuated PHI\u2010induced osteogenesis.\u00a0These findings indicate that PHI enhances BMSCs osteogenesis via the FAK\/GSK\u20103\u03b2\/\u03b2\u2010catenin axis, thereby restoring bone metabolic balance. The results highlight PHI's dual regulatory potential in the management of bone disorders, particularly, estrogen deficiency\u2010related osteoporosis, and suggest its potential applications in the therapeutic intervention of bone diseases.\n                  <\/jats:p>","DOI":"10.1002\/ptr.8519","type":"journal-article","created":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T14:29:14Z","timestamp":1755613754000},"page":"4991-5005","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Phillygenin Improves the Focal Adhesion Kinase\/Glycogen Synthase Kinase 3\u03b2\/\u03b2\u2010Catenin Axis to Promote Mesenchymal Stem Cell Osteogenic Differentiation"],"prefix":"10.1002","volume":"39","author":[{"given":"Yuchao","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Orthopedics Yue Bei People's Hospital  Shaoguan 512026 China"},{"name":"Affiliated Hospital of Youjiang Medical University for Nationalities  Baise 533000 China"},{"name":"Guangdong Provincial Key Laboratory of Digital Medical Biomechanics, National Key Discipline of Human Anatomy, Department of Anatomy School of Basic Medical Sciences, Southern Medical University  Guangzhou 510515 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haidong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Digital Medical Biomechanics, National Key Discipline of Human Anatomy, Department of Anatomy School of Basic Medical Sciences, Southern Medical University  Guangzhou 510515 China"},{"name":"Guangxi Engineering Research Center for Biomaterials in Bone and Joint Degenerative Diseases  Baise 533000 China"},{"name":"Guangxi Key Laboratory for Preclinical and Translational Research on Bone and Joint Degenerative Diseases  Baise 533000 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