{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:45:54Z","timestamp":1785415554238,"version":"3.56.0"},"reference-count":31,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100020230","name":"Jilin Provincial Health Commission","doi-asserted-by":"publisher","award":["2024A086"],"award-info":[{"award-number":["2024A086"]}],"id":[{"id":"10.13039\/501100020230","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2024A086"],"award-info":[{"award-number":["2024A086"]}],"id":[{"id":"https:\/\/ror.org\/01a67y017","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Pilotscale Selection Project of Colleges and Universities in Changchun City","award":["24GXYSZZ10"],"award-info":[{"award-number":["24GXYSZZ10"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Background: Glucocorticoid-induced osteoporosis (GIOP) is marked by impaired osteogenesis and reduced bone formation. Isobavachin (IBA), a flavonoid from Psoralea corylifolia, shows multiple potentials in anti-inflammatory and bone metabolism regulations, but its effects against GIOP remain unclear. This study investigated the osteoprotective effects and potential mechanism of IBA using zebrafish GIOP model. Methods: osteoprotective effects of IBA was assessed by fluorescence imaging in a prednisolone-induced zebrafish model, following with osteogenic gene expressions measured by RT-qPCR. Potential targets and pathways of IBA was filtered and predicted by network pharmacology, molecular docking, and molecular dynamics (MD) simulations, and finally validated with a pharmacological rescue experiment using a PI3K-specific inhibitor. Results: IBA improved bone mineralization and upregulated osteogenesis-related genes. Network pharmacology identified the PI3K-Akt pathway as a key pathway, with ESR1, GSK3B, MTOR, and CCND1 as core targets. PI3K inhibition attenuated the osteoprotective effects of IBA and suppressed downstream osteogenic gene expression. Conclusions: IBA alleviates GIOP by modulating the ESR1-associated PI3K-Akt signaling pathway and may serve as a multi-target therapeutic candidate for osteoporosis.<\/jats:p>","DOI":"10.3390\/molecules31122158","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T09:18:43Z","timestamp":1781860723000},"page":"2158","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Plant-Derived Flavonoid, Isobavachin, Promotes Osteogenesis and Alleviates Glucocorticoid-Induced Osteoporosis via Modulation of the ESR1-PI3K\/Akt Signaling Pathway"],"prefix":"10.3390","volume":"31","author":[{"given":"Jingran","family":"Cui","sequence":"first","affiliation":[{"name":"School of Integrated Chinese and Western Medicine, Changchun University of Chinese Medicine, No. 1035, Boshuo Rd, Jingyue Economic Development District, Changchun 130117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuting","family":"Song","sequence":"additional","affiliation":[{"name":"School of Integrated Chinese and Western Medicine, Changchun University of Chinese Medicine, No. 1035, Boshuo Rd, Jingyue Economic Development District, Changchun 130117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heran","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Integrated Chinese and Western Medicine, Changchun University of Chinese Medicine, No. 1035, Boshuo Rd, Jingyue Economic Development District, Changchun 130117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenhai","family":"Cui","sequence":"additional","affiliation":[{"name":"School of Integrated Chinese and Western Medicine, Changchun University of Chinese Medicine, No. 1035, Boshuo Rd, Jingyue Economic Development District, Changchun 130117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengmeng","family":"Sun","sequence":"additional","affiliation":[{"name":"Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130117, China"},{"name":"The Jilin Province School-Enterprise Cooperation Technology Innovation Laboratory of Herbal Efficacy Evaluation Based on Zebrafish Model Organisms, Changchun University of Chinese Medicine, Jingyue Economic Development District, Changchun 130117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"He","sequence":"additional","affiliation":[{"name":"Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130117, China"},{"name":"The Jilin Province School-Enterprise Cooperation Technology Innovation Laboratory of Herbal Efficacy Evaluation Based on Zebrafish Model Organisms, Changchun University of Chinese Medicine, Jingyue Economic Development District, Changchun 130117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiying","family":"Jin","sequence":"additional","affiliation":[{"name":"School of Integrated Chinese and Western Medicine, Changchun University of Chinese Medicine, No. 1035, Boshuo Rd, Jingyue Economic Development District, Changchun 130117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2547","DOI":"10.1056\/NEJMcp1800214","article-title":"Glucocorticoid-induced osteoporosis","volume":"379","author":"Buckley","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/S0140-6736(18)32112-3","article-title":"Osteoporosis","volume":"393","author":"Compston","year":"2019","journal-title":"Lancet"},{"key":"ref_3","first-page":"67","article-title":"Alpha-lipoic acid in pharmaceutical development: A comprehensive review of its therapeutic potential and molecular mechanisms","volume":"23","author":"Koyuncu","year":"2025","journal-title":"Prospect. Pharm. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"49","DOI":"10.56782\/pps.147","article-title":"Quercetin: Derivatives, biosynthesis, biological activity, pharmacological and therapeutic effects","volume":"21","author":"Mohammed","year":"2023","journal-title":"Prospect. Pharm. Sci."},{"key":"ref_5","first-page":"17","article-title":"A novel targeted formulation for osteoarthritis: Exploring synergistic benefits of Cissus quadrangularis, Boswellia serrata, propolis and palmitoylethanolamide","volume":"24","author":"Dharani","year":"2026","journal-title":"Prospect. Pharm. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Xin, C., Zhang, G., Shen, Z., Han, W., Fan, R., Ren, J., Zhang, J., Hao, Y., and Xin, J. (2025). Pharmacological mechanism of natural products to treat osteoporosis: A focus on the autophagy. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1623990"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/1749-8546-7-10","article-title":"Kaempferol as a flavonoid induces osteoblastic differentiation via estrogen receptor signaling","volume":"7","author":"Guo","year":"2012","journal-title":"Chin. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"116202","DOI":"10.1016\/j.bcp.2024.116202","article-title":"Isobavachin attenuates osteoclastogenesis and periodontitis-induced bone loss by inhibiting cellular iron accumulation and mitochondrial biogenesis","volume":"224","author":"Li","year":"2024","journal-title":"Biochem. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Noor, F., Tahir Ul Qamar, M., Ashfaq, U.A., Albutti, A., Alwashmi, A.S.S., and Aljasir, M.A. (2022). Network Pharmacology Approach for Medicinal Plants: Review and Assessment. Pharmaceuticals, 15.","DOI":"10.3390\/ph15050572"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"14755","DOI":"10.1038\/s41598-024-64769-z","article-title":"Integration of molecular docking and molecular dynamics simulations with subtractive proteomics approach to identify the novel drug targets and their inhibitors in Streptococcus gallolyticus","volume":"14","author":"Chao","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Tonelli, F., Bek, J.W., Besio, R., De Clercq, A., Leoni, L., Salmon, P., Coucke, P.J., Willaert, A., and Forlino, A. (2020). Zebrafish: A resourceful vertebrate model to investigate skeletal disorders. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.00489"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1002\/dvg.20639","article-title":"Zebrafish sp7: EGFP: A transgenic for studying otic vesicle formation, skeletogenesis, and bone regeneration","volume":"48","author":"DeLaurier","year":"2010","journal-title":"Genesis"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Liu, Q., Li, M., Wang, S., Xiao, Z., Xiong, Y., and Wang, G. (2020). Recent advances of osterix transcription factor in osteoblast differentiation and bone formation. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.601224"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Du, J., Wang, Y., Wu, C., Zhang, X., Zhang, X., and Xu, X. (2024). Targeting bone homeostasis regulation: Potential of traditional Chinese medicine flavonoids in the treatment of osteoporosis. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1361864"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1002\/jcb.24646","article-title":"Glucocorticoids antagonize RUNX2 during osteoblast differentiation in cultures of ST2 pluripotent mesenchymal cells","volume":"115","author":"Koromila","year":"2014","journal-title":"J. Cell. Biochem."},{"key":"ref_16","first-page":"189","article-title":"Chemical and biochemical basis of cell-bone matrix interaction in health and disease","volume":"3","author":"Feng","year":"2009","journal-title":"Curr. Chem. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/nrm3254","article-title":"Building strong bones: Molecular regulation of the osteoblast lineage","volume":"13","author":"Long","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"197","DOI":"10.3109\/03008209609029192","article-title":"Osteopontin: An interfacial extracellular matrix protein in mineralized tissues","volume":"35","author":"Mckee","year":"1996","journal-title":"Connect. Tissue Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1172\/JCI65910","article-title":"Estrogen receptor-\u03b1 signaling in osteoblast progenitors stimulates cortical bone accrual","volume":"123","author":"Almeida","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"91","DOI":"10.4048\/jbc.2006.9.2.91","article-title":"Up-regulation of Pi3k\/Akt Signaling by 17\u03b2-estradiol through Activation Of Estrogen Receptor-\u03b1 in Breast Cancer Cells","volume":"9","author":"So","year":"2006","journal-title":"J. Breast Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/978-3-319-56895-9_6","article-title":"Estrogen receptors in cell membranes: Regulation and signaling","volume":"227","author":"Saczko","year":"2017","journal-title":"Adv. Anat. Embryol. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"112137","DOI":"10.1016\/j.yexcr.2020.112137","article-title":"The PI3K\/AKT pathway promotes fracture healing through its crosstalk with Wnt\/\u03b2-catenin","volume":"394","author":"Dong","year":"2020","journal-title":"Exp. Cell Res."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Liu, C., Zhang, J., Ye, Z., Luo, J., Peng, B., and Wang, Z. (2025). Research on the role and mechanism of the PI3K\/Akt\/mTOR signalling pathway in osteoporosis. Front. Endocrinol., 16.","DOI":"10.3389\/fendo.2025.1541714"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s13578-023-00988-7","article-title":"Cell cycle regulators and bone: Development and regeneration","volume":"13","author":"Shaikh","year":"2023","journal-title":"Cell Biosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.nutres.2017.04.009","article-title":"Daidzein stimulates osteogenesis facilitating proliferation, differentiation, and antiapoptosis in human osteoblast-like MG-63 cells via estrogen receptor\u2013dependent MEK\/ERK and PI3K\/Akt activation","volume":"42","author":"Jin","year":"2017","journal-title":"Nutr. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e70135","DOI":"10.1111\/cbdd.70135","article-title":"Anti-Osteoporosis Activity of Lycopene Through ESR1: Network Pharmacology, Molecular Docking, Imaging Technology, and Experimental Validation","volume":"105","author":"Zhao","year":"2025","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Hu, H.-Y., Zhang, Z.-Z., Jiang, X.-Y., Duan, T.-H., Feng, W., and Wang, X.-G. (2023). Hesperidin anti-osteoporosis by regulating estrogen signaling pathways. Molecules, 28.","DOI":"10.3390\/molecules28196987"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"117501","DOI":"10.1016\/j.jep.2023.117501","article-title":"Isobavachin, a main bioavailable compound in Psoralea corylifolia, alleviates lipopolysaccharide-induced inflammatory responses in macrophages and zebrafish by suppressing the MAPK and NF-\u03baB signaling pathways","volume":"321","author":"Chung","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1007\/s12020-013-9894-1","article-title":"Impaired PI3 K Akt expression in liver and skeletal muscle of ovariectomized rats","volume":"44","author":"Wang","year":"2013","journal-title":"Endocrine"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"S60","DOI":"10.1016\/j.molmet.2019.06.012","article-title":"Endoplasmic reticulum stress, degeneration of pancreatic islet \u03b2-cells, and therapeutic modulation of the unfolded protein response in diabetes","volume":"27","author":"Ghosh","year":"2019","journal-title":"Mol. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"334ra354","DOI":"10.1126\/scitranslmed.aad3815","article-title":"Skeletal muscle action of estrogen receptor \u03b1 is critical for the maintenance of mitochondrial function and metabolic homeostasis in females","volume":"8","author":"Ribas","year":"2016","journal-title":"Sci. Transl. Med."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/12\/2158\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T09:19:22Z","timestamp":1781860762000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/12\/2158"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,18]]},"references-count":31,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["molecules31122158"],"URL":"https:\/\/doi.org\/10.3390\/molecules31122158","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,18]]}}}