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While the WW domain\u2010containing coiled\u2010coil adaptor (WAC) protein is primarily associated with transcriptional regulation and autophagy, its involvement in MSC osteogenesis remains unclear. Here, the data reveal that the levels of WAC are diminished in both osteoporosis patients and osteoporosis mouse models. It plays a pivotal function in facilitating MSC osteogenesis and enhancing new bone formation both in vitro and in vivo. Mechanistically, WAC promotes MSC osteogenesis by protecting PINK1, a crucial initiator of mitophagy, from ubiquitination\u2010dependent degradation thereby activating mitophagy. Interestingly, WAC interacts with the TM domains of PINK1 and prevents the K137 site from ubiquitination modification. The study elucidates the mechanism by which WAC modulates MSC osteogenesis, binds to PINK1 to protect it from ubiquitination, and identifies potential therapeutic targets for osteoporosis and bone defect repair.<\/jats:p>","DOI":"10.1002\/advs.202404107","type":"journal-article","created":{"date-parts":[[2024,11,18]],"date-time":"2024-11-18T07:10:52Z","timestamp":1731913852000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["WAC Facilitates Mitophagy\u2010mediated MSC Osteogenesis and New Bone Formation via Protecting PINK1 from Ubiquitination\u2010Dependent Degradation"],"prefix":"10.1002","volume":"12","author":[{"given":"Shuai","family":"Fan","sequence":"first","affiliation":[{"name":"Department of Orthopedics The Eighth Affiliated Hospital Sun Yat\u2010sen University  Shenzhen 518033 P. R. 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