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In this study, we identified WD40 repeat-containing protein 23 (WDR23), also known as DDB1-CUL4 associated factor 11 (DCAF11), as a novel binding partner of TRAF6. Our findings demonstrate that WDR23\/DCAF11 acts as a negative feedback regulator of RANK\/RANKL-induced osteoclastogenesis by promoting the autophagy-dependent degradation of TRAF6. Notably, RANKL induced the upregulation of WDR23 expression during osteoclastogenesis. WDR23 physically interacted with the TRAF domain of TRAF6 via the WD40 repeat domains 1 and 2 of WDR23, resulting in reduced TRAF6 protein stability by its autophagy-dependent degradation during osteoclastogenesis. By modulating TRAF6 protein levels, WDR23 attenuated RANKL signaling cascades, including nuclear factor-\u03baB and mitogen-activated protein kinases, thereby downregulating the expression of osteoclastogenic markers, such as nuclear factor of activated T-cell c1, tartrate-resistant acid phosphatase, dendritic cell-specific transmembrane protein, V-ATPase subunit d2 and cathepsin K. Conversely, WDR23 knockdown or deficiency enhanced RANKL-induced osteoclastogenesis by preventing the autophagy-dependent degradation of TRAF6. WDR23-deficient mice exhibit an osteoporotic bone phenotype characterized by elevated osteoclast formation and reduced bone mass. Collectively, these results establish WDR23 as a key negative feedback regulator of RANKL-induced osteoclastogenesis via autophagy-mediated TRAF6 degradation and underscore its potential as a therapeutic target for bone disorders associated with aberrant osteoclast formation and function.<\/jats:p>","DOI":"10.1038\/s41413-026-00560-2","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T02:56:36Z","timestamp":1789008996000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["WDR23 prevents bone loss by promoting autophagic degradation of TRAF6 in osteoclastogenesis"],"prefix":"10.1038","volume":"14","author":[{"given":"Hye-Won","family":"Park","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jungeun","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiyeon","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinseon","family":"You","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeon Hee","family":"Kook","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1049-6006","authenticated-orcid":false,"given":"Joo-Yong","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taesoo","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6996-5746","authenticated-orcid":false,"given":"Chul-Ho","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hee-Chung","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong-Soon","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sangkyu","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0019-4939","authenticated-orcid":false,"given":"Jaerang","family":"Rho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"560_CR1","doi-asserted-by":"publisher","first-page":"2851","DOI":"10.3390\/ijms22062851","volume":"22","author":"DS Amarasekara","year":"2021","unstructured":"Amarasekara, D. 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