{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T11:49:46Z","timestamp":1778586586775,"version":"3.51.4"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T00:00:00Z","timestamp":1768176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012547","name":"Natural Science Foundation of Guangxi Zhuang Autonomous Region","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012547","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"\n Background<\/jats:title>\n Postmenopausal osteoporosis (PMOP), driven predominantly by estrogen deficiency-induced hyperactivation of osteoclasts, represents a critical public health burden. The pursuit of naturally sourced inhibitors of osteoclast function with minimized adverse effects remains a pivotal research endeavor. \u03b3-Mangostin (\u03b3-Mag), a natural xanthone derived from the pericarp of mangosteen, possesses broad anti-inflammatory and anti-tumor activities. Nevertheless, its influence on bone metabolic homeostasis, particularly osteoclast biology, remains entirely unexplored. This study aims to elucidate the impact of \u03b3-Mag on osteoclast differentiation and function, and to evaluate its therapeutic potential for PMOP.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Primary rat bone marrow-derived macrophages (BMMs) were isolated and stimulated with RANKL to establish an\n in vitro<\/jats:italic>\n osteoclastogenesis model. The effects of \u03b3-Mag on osteoclast formation and function were assessed through TRAP staining, F-actin ring immunofluorescence, and bone slice resorption pit assays. Mechanistic insights were gained by examining the PI3K\/Akt\/NF-\u03baB pathway and downstream osteoclastogenic factors (C-FOS, NFATc1) using qRT-PCR, Western blot, and immunofluorescence. The\n in vivo<\/jats:italic>\n efficacy was validated in an ovariectomized (OVX) rat model of PMOP, with bone microarchitecture and remodeling parameters analyzed\n via<\/jats:italic>\n Micro-CT and bone histomorphometry.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n At non-cytotoxic concentrations (\u22644\u00a0\u03bcM), \u03b3-Mag potently and concentration-dependently suppressed RANKL-induced osteoclast formation, disrupted F-actin ring integrity, and impaired bone resorptive activity. Mechanistically, \u03b3-Mag significantly attenuated the RANKL-triggered activation of the PI3K\/AKT\/NF-\u03baB signaling axis, as demonstrated by reduced phosphorylation of PI3K, AKT, p65, and I\u03baB. This upstream suppression consequently led to the downregulation of the pivotal transcription factors C-FOS and NFATc1, and inhibited NFATc1 nuclear translocation.\n In vivo<\/jats:italic>\n , \u03b3-Mag administration (10\u00a0mg\/kg, i.p., every other day for 8\u00a0weeks) markedly ameliorated bone loss and restored compromised bone microarchitecture in OVX rats, which was associated with reduced osteoclast numbers and decreased expression of\n ACP5<\/jats:italic>\n ,\n CTSK<\/jats:italic>\n ,\n C-FOS<\/jats:italic>\n , and\n NFATc1<\/jats:italic>\n in bone tissue.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n Our findings demonstrate that \u03b3-Mag inhibits osteoclastogenesis and bone resorption by targeting the PI3K\/AKT\/NF-\u03baB pathway, thereby blunting the C-FOS\/NFATc1 transcriptional program. This study establishes \u03b3-Mag as a promising natural lead compound for the treatment of postmenopausal osteoporosis.<\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fphar.2025.1742401","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T08:19:52Z","timestamp":1768205992000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["\u03b3-Mangostin attenuates osteoclastogenesis and bone resorption by suppressing the PI3K\/AKT\/NF-\u03baB pathway"],"prefix":"10.3389","volume":"16","author":[{"given":"Jian","family":"Wei","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiayue","family":"Xie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiyang","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaofeng","family":"Feng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.lfs.2016.01.024","article-title":"Natural products for treatment of osteoporosis: the effects and mechanisms on promoting osteoblast-mediated bone formation","volume":"147","author":"An","year":"2016","journal-title":"Life Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/j.bone.2006.09.023","article-title":"The molecular understanding of osteoclast differentiation","volume":"40","author":"Asagiri","year":"2007","journal-title":"Bone"},{"key":"B3","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1002\/jbmr.1885","article-title":"Advances in osteoclast biology reveal potential new drug targets and new roles for osteoclasts","volume":"28","author":"Boyce","year":"2013","journal-title":"J. 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