{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T22:23:13Z","timestamp":1779920593491,"version":"3.53.1"},"reference-count":38,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T00:00:00Z","timestamp":1762300800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T00:00:00Z","timestamp":1762300800000},"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":["The Kaohsiung J of Med Scie"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Osteoarthritis (OA) is a prevalent degenerative joint disease. This study combines bioinformatics analysis with in\u00a0vivo and in\u00a0vitro experiments to elucidate the molecular mechanisms through which melatonin (MT) regulates mitophagy to alleviate OA. Rat and chondrocyte OA models were established via anterior cruciate ligament transection or interleukin (IL)\u20101\u03b2 induction, followed by treatment with MT, Cyclosporine A (a mitophagy inhibitor), and 740Y\u2010P (a phosphatidylinositol\u20103 kinase [PI3K] activator). Pathological changes in cartilage, histological scores, and cell apoptosis were evaluated alongside chondrocyte viability, apoptosis, mitochondrial morphology, mitochondrial membrane potential, and mitophagy using H&amp;E and Safranin O\u2010fast green staining, Osteoarthritis Research Society International scoring (OARSI), TUNEL staining, CCK\u20108, flow cytometry, transmission electron microscopy, JC\u20101 staining, and immunofluorescence. Levels of inflammatory factors and mitophagy\u2010related protein levels were determined by ELISA and western blot. Bioinformatics analysis was applied to investigate the regulatory mechanisms of MT on mitophagy in OA. In\u00a0vivo, MT mitigated OA by enhancing mitophagy and reducing apoptosis of cartilage cells. In\u00a0vitro, MT attenuated IL\u20101\u03b2\u2010induced chondrocyte apoptosis through mitophagy activation, and this effect was partially reversed by mitophagy inhibition. Mechanistically, the PI3K\/protein kinase B (AKT)\/forkhead box O3 (FoxO3) axis appeared to play a central role. MT suppressed PI3K\/AKT signaling, thereby upregulating FoxO3 expression and promoting mitophagy, ultimately reducing chondrocyte apoptosis. Collectively, these findings suggest that MT enhances mitophagy via inhibition of the PI3K\/AKT pathway, and subsequent upregulation of FoxO3, leading to reduced apoptosis of cartilage cells and attenuation of OA progression in rats.<\/jats:p>","DOI":"10.1002\/kjm2.70131","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T12:43:35Z","timestamp":1762346615000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Melatonin Exerts Chondroprotective Effects Against Osteoarthritis by Promoting\n                    <scp>PI3K<\/scp>\n                    \/\n                    <scp>AKT<\/scp>\n                    \/\n                    <scp>FoxO3<\/scp>\n                    \u2010Mediated Mitophagy"],"prefix":"10.1002","volume":"42","author":[{"given":"Chao","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Orthopedics The Second Affiliated Hospital of Harbin Medical University  Harbin China"},{"name":"The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Emergency Medicine Center (Emergency Surgery), affiliated Hospital of Guangdong Medical University  Zhanjiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying\u2010Kai","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Orthopedics The Second Affiliated Hospital of Harbin Medical University  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin\u2010Nan","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Orthopedics The Second Affiliated Hospital of Harbin Medical University  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4343-5892","authenticated-orcid":false,"given":"Song\u2010Cen","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Orthopedics The Second Affiliated Hospital of Harbin Medical University  Harbin 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