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Although melatonin exhibits bone\u2011anabolic properties, its mechanistic role in the context of mechanical unloading remains elusive. Our findings demonstrate that melatonin promotes osteogenic differentiation and suppresses osteoblast apoptosis, collectively mitigating unloading\u2011induced osteoporotic bone loss in hindlimb unloading (HLU) mice. Moreover, unloading suppressed YTHDF3 expression in osteoblasts and bone tissue, which was effectively rescued by melatonin administration. Functionally, YTHDF3 potentiated osteoblast differentiation and matrix mineralization while inhibiting apoptotic cell death. At the molecular level, YTHDF3 directly recognized m\n                    <jats:sup>6<\/jats:sup>\n                    A\u2011modified\n                    <jats:italic>Dapk2<\/jats:italic>\n                    transcripts and promoted their decay. DAPK2 was characterized as a negative regulator that impedes osteoblast differentiation and survival. Genetic analyses established that melatonin\u2011driven suppression of DAPK2 and functional recovery of osteoblasts are contingent upon YTHDF3. In summary, we delineate a melatonin\/YTHDF3\/DAPK2 protective axis that safeguards against unloading\u2011induced bone deterioration via post\u2011transcriptional regulation of\n                    <jats:italic>Dapk2<\/jats:italic>\n                    , thereby unveiling new mechanistic perspectives and therapeutic opportunities for disuse osteoporosis.\n                  <\/jats:p>","DOI":"10.1111\/jpi.70146","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T14:31:20Z","timestamp":1779114680000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Melatonin Counteracts Mechanical Unloading\u2010Induced Bone Loss Through YTHDF3\u2010Mediated m\n                    <sup>6<\/sup>\n                    A Modification of\n                    <i>Dapk2<\/i>\n                    mRNA"],"prefix":"10.1111","volume":"78","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-3861-3416","authenticated-orcid":false,"given":"Quan","family":"Sun","sequence":"first","affiliation":[{"name":"The Key Laboratory of Aerospace Medicine, Ministry of Education The Fourth Military Medical University Xi'an Shaanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqun","family":"Xu","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Aerospace Medicine, Ministry of Education The Fourth Military Medical University Xi'an Shaanxi China"},{"name":"Department of Gastroenterology and Endocrinology Western Theater Air Force Hospital of PLA Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhikui","family":"Li","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Aerospace Medicine, Ministry of Education The Fourth Military Medical University Xi'an Shaanxi 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