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Currently, drug\u2010targeting osteoclasts show promising therapy for osteoporosis. In this study, we investigated the effect of cichoric acid (CA) on receptor activator of nuclear kappa\u2010B ligand (RANKL)\u2010induced osteoclastogenesis and the bone loss induced by ovariectomy in mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Procedure<\/jats:title>\n                    <jats:p>Molecular docking technologies were employed to examine the interaction between CA and RANKL. CCK8 assay was used to evaluate the cell viability under CA treatment. TRAcP staining, podosome belt staining, and bone resorption assays were used to test the effect of CA on osteoclastogenesis and osteoclast function. Further, an OVX\u2010induced osteoporosis mice model was employed to identify the effect of CA on bone loss using micro\u2010CT scanning and histological examination. To investigate underlying mechanisms, network pharmacology was applied to predict the downstream signaling pathways, which were verified by Western blot and immunofluorescence staining.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>The molecular docking analysis revealed that CA exhibited a specific binding affinity to RANKL, engaging multiple binding sites. CA inhibited RANKL\u2010induced osteoclastogenesis and bone resorption without cytotoxic effects. Mechanistically, CA suppressed RANKL\u2010induced intracellular reactive oxygen species, nuclear factor\u2010kappa B, and mitogen\u2010activated protein kinase pathways, followed by abrogated nuclear factor activated T\u2010cells 1 activity. Consistent with this finding, CA attenuated post\u2010ovariectomy\u2010induced osteoporosis by ameliorating osteoclastogenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>CA inhibited osteoclast activity and bone loss by targeting RANKL. CA might represent a promising candidate for treating osteoclast\u2010related diseases, such as osteoporosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ptr.8141","type":"journal-article","created":{"date-parts":[[2024,2,15]],"date-time":"2024-02-15T11:19:41Z","timestamp":1707995981000},"page":"1971-1989","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Cichoric acid targets\n                    <scp>RANKL<\/scp>\n                    to inhibit osteoclastogenesis and prevent\n                    <scp>ovariectomy<\/scp>\n                    \u2010induced bone loss"],"prefix":"10.1002","volume":"38","author":[{"given":"Yansi","family":"Xian","sequence":"first","affiliation":[{"name":"Guangxi Key Laboratory of Regenerative Medicine, Orthopaedics Trauma and Hand Surgery The First Affiliated Hospital of Guangxi Medical University  Nanning China"},{"name":"Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co\u2010constructed by the Province and Ministry Guangxi Medical University  Nanning China"},{"name":"Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijie","family":"Gao","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Regenerative Medicine, Orthopaedics Trauma and Hand Surgery The First Affiliated Hospital of Guangxi Medical University  Nanning China"},{"name":"Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co\u2010constructed by the Province and Ministry Guangxi Medical University  Nanning 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