{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T08:54:00Z","timestamp":1776416040228,"version":"3.51.2"},"reference-count":20,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"WKU-ISRG","award":["ISRG2023032"],"award-info":[{"award-number":["ISRG2023032"]}]},{"name":"International Frontier Interdisciplinary Research Institute","award":["KY20250604000450"],"award-info":[{"award-number":["KY20250604000450"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Osteoclast hyperactivity represents a central mechanism in pathological bone destruction, underscoring the importance of discovering novel anti-resorptive compounds. In this study, we present early-stage evidence that 8-Epixanthatin can inhibit osteoclast differentiation induced by receptor activator of nuclear factor kappa-B ligand (RANKL). 8-Epixanthatin exhibited no significant cytotoxicity at the concentrations used for osteoclast differentiation studies. The compound showed concentration-dependent reductions in TRAP-positive multinucleated osteoclasts, with an IC50 value of 2.3 \u03bcM. Our mechanistic investigations revealed that 8-Epixanthatin interferes with RANKL-activated signaling networks, particularly nuclear factor kappa-B (NF-\u03baB) and mitogen-activated protein kinase (MAPK) cascades. Collectively, these observations identify 8-Epixanthatin as a promising lead structure for anti-osteoclast drug discovery.<\/jats:p>","DOI":"10.3390\/ijms27083578","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T07:48:12Z","timestamp":1776412092000},"page":"3578","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["8-Epixanthatin Suppresses RANKL-Induced Osteoclast Differentiation via Inhibition of NF-\u03baB and MAPK Signaling"],"prefix":"10.3390","volume":"27","author":[{"given":"Lifang","family":"Zhang","sequence":"first","affiliation":[{"name":"Osteoimmunology and Drug Discovery Research Group, Department of Biology, College of Science, Mathematics and Technology, Wenzhou-Kean University, 88 Daxue Road, Wenzhou 325060, China"},{"name":"Dorothy and George Hennings College of Science, Mathematics and Technology, Kean University, 1000 Morris Ave, Union, NJ 07083, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0148-255X","authenticated-orcid":false,"given":"Vishwa","family":"Deepak","sequence":"additional","affiliation":[{"name":"Osteoimmunology and Drug Discovery Research Group, Department of Biology, College of Science, Mathematics and Technology, Wenzhou-Kean University, 88 Daxue Road, Wenzhou 325060, China"},{"name":"Dorothy and George Hennings College of Science, Mathematics and Technology, Kean University, 1000 Morris Ave, Union, NJ 07083, USA"},{"name":"International Frontier Interdisciplinary Research Institute (IFIRI), Wenzhou-Kean University, Wenzhou 325060, China"},{"name":"Wenzhou Municipal Key Laboratory for Applied Biomedical and Biopharmaceutical Informatics, Wenzhou-Kean University, Ouhai, Wenzhou 325060, China"},{"name":"Zhejiang Bioinformatics International Science and Technology Cooperation Center, Wenzhou-Kean University, Ouhai, Wenzhou 325060, China"},{"name":"Zhejiang-Malaysia Joint Laboratory for Rare Medicinal Resources, Wenzhou-Kean University, 88 Daxue Road, Ouhai, Wenzhou 325060, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1038\/s41413-022-00219-8","article-title":"Bone remodeling: An operational process ensuring survival and bone mechanical competence","volume":"10","author":"Bolamperti","year":"2022","journal-title":"Bone Res."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Terkawi, M.A., Matsumae, G., Shimizu, T., Takahashi, D., Kadoya, K., and Iwasaki, N. (2022). Interplay between Inflammation and Pathological Bone Resorption: Insights into Recent Mechanisms and Pathways in Related Diseases for Future Perspectives. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031786"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/S1534-5807(02)00369-6","article-title":"Induction and Activation of the Transcription Factor NFATc1 (NFAT2) Integrate RANKL Signaling in Terminal Differentiation of Osteoclasts","volume":"3","author":"Takayanagi","year":"2002","journal-title":"Dev. Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/nature01658","article-title":"Osteoclast differentiation and activation","volume":"423","author":"Boyle","year":"2003","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Walsh, M.C., and Choi, Y. (2014). Biology of the RANKL\u2013RANK\u2013OPG system in immunity, bone, and beyond. Front. Immunol., 5.","DOI":"10.3389\/fimmu.2014.00511"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1152\/physiol.00031.2024","article-title":"Role of RANKL Signaling in Bone Homeostasis","volume":"40","author":"Sobacchi","year":"2025","journal-title":"Physiology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"16069","DOI":"10.1038\/nrdp.2016.69","article-title":"Postmenopausal osteoporosis","volume":"2","author":"Eastell","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.ejmech.2014.11.060","article-title":"Optimization of xanthatin extraction from Xanthium spinosum L. and its cytotoxic, anti-angiogenesis and antiviral properties","volume":"90","author":"Romero","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3523","DOI":"10.3390\/molecules19033523","article-title":"Structure-Activity Relationship Study of Sesquiterpene Lactones and Their Semi-Synthetic Amino Derivatives as Potential Antitrypanosomal Products","volume":"19","author":"Zimmermann","year":"2014","journal-title":"Molecules"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/S1074-5521(01)00049-7","article-title":"The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits I\u03baB kinase","volume":"8","author":"Kwok","year":"2001","journal-title":"Chem. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"33508","DOI":"10.1074\/jbc.273.50.33508","article-title":"The Anti-inflammatory Sesquiterpene Lactone Helenalin Inhibits the Transcription Factor NF-\u03baB by Directly Targeting p65","volume":"273","author":"Knorre","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s00774-020-01191-1","article-title":"RANKL as the master regulator of osteoclast differentiation","volume":"39","author":"Takayanagi","year":"2021","journal-title":"J. Bone Miner. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Liu, Y., Chen, W., Zheng, F., Yu, H., and Wei, K. (2022). Xanthatin Alleviates LPS-Induced Inflammatory Response in RAW264.7 Macrophages by Inhibiting NF-\u03baB, MAPK and STATs Activation. Molecules, 27.","DOI":"10.3390\/molecules27144603"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"116451","DOI":"10.1016\/j.biopha.2024.116451","article-title":"Targeted inhibition of STAT3 (Tyr705) by xanthatin alleviates osteoarthritis progression through the NF-\u03baB signaling pathway","volume":"174","author":"Xu","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2849","DOI":"10.1016\/S0968-0896(99)00234-5","article-title":"Helenanolide type sesquiterpene lactones. Part 5: The role of glutathione addition under physiological conditions","volume":"7","author":"Schmidt","year":"1999","journal-title":"Bioorg. Med. Chem."},{"key":"ref_16","first-page":"1063","article-title":"Side effects of drugs for osteoporosis and metastatic bone disease","volume":"85","author":"Frost","year":"2018","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.jss.2013.10.027","article-title":"Parthenolide inhibits polyethylene particle\u2013induced mouse calvarial osteolysis in vivo","volume":"187","author":"Li","year":"2014","journal-title":"J. Surg. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e2201490119","DOI":"10.1073\/pnas.2201490119","article-title":"IFT80 negatively regulates osteoclast differentiation via association with Cbl-b to disrupt TRAF6 stabilization and activation","volume":"119","author":"Deepak","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/s12272-016-0790-0","article-title":"Ellagic acid inhibits RANKL-induced osteoclast differentiation by suppressing the p38 MAP kinase pathway","volume":"40","author":"Rantlha","year":"2016","journal-title":"Arch. Pharmacal Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1248\/bpb.b16-00117","article-title":"Carvacrol Inhibits Osteoclastogenesis and Negatively Regulates the Survival of Mature Osteoclasts","volume":"39","author":"Deepak","year":"2016","journal-title":"Biol. Pharm. 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