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Therefore, the development of natural compounds that aim at the crucial regulator of the aforementioned pathway is essential for the suppression of osteoclastogenesis and its clinical application. Skimmianine (Ski), a furoquinoline alkaloid extracted from the Zanthoxylum genus, is known for its anti\u2010inflammatory properties. Yet, its exact role in osteoclast differentiation and function remains largely undefined. Herein, we evaluate the impact of Ski on osteoclastogenesis and elucidate the molecular mechanism involved. We conducted network pharmacology and molecule structure\u2010based pharmacokinetics analyses on Ski, followed by experimental validations on osteoclastogenesis in\u00a0vitro and ovariectomy (OVX) mice model in\u00a0vivo. The network pharmacology results indicated Ski's therapeutic effects predominantly influence the calcium signalling pathway by controlling cytosolic calcium concentration in response to bone resorption during osteoporosis. Pharmacokinetic analyses revealed Ski's excellent oral bioavailability. Furthermore, experimental validations revealed that Ski inhibited the formation of multinucleated osteoclasts in a concentration\u2010dependent manner without affecting cell viability, while impeding osteoclast\u2010related gene expression. The underlying mechanism involved the Ski\u2010induced downregulation of calcineurin\/Nfatc1 expression through modulation of ERp57\u2010driven calcium oscillations. Micro\u2010CT results confirmed that Ski treatment substantially curbed the progression of osteoporosis by mitigating bone loss. In conclusion, our findings indicated that Ski suppressed osteoclast formation by suppressing ERp57\u2010driven calcium oscillations\/calcineurin\/Nfatc1 signalling, thus establishing Ski as a promising therapeutic alternative for osteoporosis.<\/jats:p>","DOI":"10.1111\/jcmm.70777","type":"journal-article","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T03:50:43Z","timestamp":1755057043000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Skimmianine Attenuates Osteoclast Activity by Suppressing\n                    <scp>ERp57\u2010<\/scp>\n                    Driven Calcium Oscillations\/Calcineurin\/Nfatc1 Signalling in Postmenopausal Osteoporosis"],"prefix":"10.1111","volume":"29","author":[{"given":"Yongshuang","family":"Lv","sequence":"first","affiliation":[{"name":"Department of Joint Surgery Shandong Provincial Hospital Affiliated to Shandong First Medical University  Jinan Shandong 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