{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T20:22:56Z","timestamp":1790886176051,"version":"4.1.0"},"reference-count":57,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T00:00:00Z","timestamp":1771286400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T00:00:00Z","timestamp":1771286400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Phytotherapy Research"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2010sitosterol, a phytosterol widely distributed in Chinese herbal medicines, exhibits significant anti\u2010inflammatory and antioxidant activities. This study aimed to investigate the potential role of\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2010sitosterol in osteoclastogenesis and bone loss. Primary BMDM were used to induce osteoclastogenesis and evaluate the effect of\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2010sitosterol on osteoclastogenesis. Meanwhile, an ovariectomy\u2010induced osteoporosis mouse model was employed to examine the effect of\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2010sitosterol on bone mass in\u00a0vivo. The results indicated that the MAPK and Hedgehog signaling pathways were identified as key signaling pathways, with Tmed10 recognized as the drug target protein. In\u00a0vitro experiments demonstrated that\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2010sitosterol suppressed RANKL\u2010induced osteoclastogenesis and cytoskeleton formation in a concentration\u2010dependent manner, downregulated the expression of osteoclast\u2010related genes and proteins, and inhibited the nuclear translocation of NFATc1. Mechanistically,\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2010sitosterol inhibited the phosphorylation of ERK in the MAPK pathway and the nuclear translocation of p\u2010ERK. Concurrently,\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2010sitosterol suppressed cellular and mitochondrial ROS generation and upregulated the expression of antioxidant enzymes. CETSA demonstrated that\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2010sitosterol protects Tmed10 from thermal degradation, while the DARTS assay confirmed that\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2010sitosterol binds to Tmed10 and prevents its enzymatic digestion. These results verified the direct binding between Tmed10 and\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2010sitosterol. Co\u2010immunoprecipitation indicated that Tmed10 directly interacts with HHIP, thereby inhibiting the activation of the downstream Hedgehog signaling pathway. In\u00a0vivo studies revealed that administration of\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2010sitosterol activated Tmed10 expression, attenuated osteoclastogenesis, improved bone microstructure and trabecular parameters, and prevented ovariectomy\u2010induced bone loss. In conclusion,\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2010sitosterol effectively suppresses osteoclastogenesis and rescues bone loss by targeting Tmed10 to regulate the key MAPK\/Hedgehog signaling pathways and reduce ROS generation. The significant protective effect of\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2010sitosterol against bone loss in\u00a0vivo suggests its potential as a candidate therapeutic agent for osteoporosis.\n                  <\/jats:p>","DOI":"10.1002\/ptr.70263","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T06:56:01Z","timestamp":1771397761000},"page":"2491-2513","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["<i>\u03b2<\/i>\n                    \u2010Sitosterol Suppresses Osteoclastogenesis and Alleviates Bone Loss by Targeting Tmed10 to Inhibit\n                    <scp>RANKL<\/scp>\n                    \u2010Induced Hedgehog\/\n                    <scp>MAPK<\/scp>\n                    Signaling and\n                    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