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The ketogenic diet (KD) has been postulated to impede the advancement of various inflammatory ailments. \u03b2\u2010Hydroxybutyrate (\u03b2OHB), a prominent constituent of ketone bodies, has recently been proposed to possess crucial signaling capabilities. In this study, we propose to explore the role and mechanism of \u03b2OHB in OA. Tissue staining and inflammatory factor assay were employed to evaluate the impacts of KD and \u03b2OHB on OA rats. The oxidative stress conditions in chondrocytes were induced using tert\u2010butyl hydroperoxide (TBHP). The mechanisms were determined using the siRNA of hydroxycarboxylic acid receptor 2 (HCAR2), the antagonist of adenosine monophosphate\u2010activated protein kinase (AMPK), and the inhibitor of mitophagy. The administration of KD demonstrated a reduction in pathological damage to cartilage, as well as a decrease in plasma levels of inflammatory factors. Furthermore, it resulted in an increase in the concentration of \u03b2OHB in the blood and synovial fluid. In\u00a0vitro experiments showed that \u03b2OHB facilitated mitophagy and adenosine triphosphate production. Besides, \u03b2OHB mitigated chondrocyte senescence, inflammatory factors secretion, extracellular matrix degradation, and apoptosis induced by TBHP. Subsequent investigations indicated that the protective effects of \u03b2OHB were no longer observed following the knockdown of HCAR2, the antagonist of AMPK, or the inhibitor of mitophagy. Moreover, in\u00a0vivo studies suggested that \u03b2OHB played a protective role by targeting the HCAR2\u2010AMPK\u2010PINK1 axis. In conclusion,\u00a0\u03b2OHB enhanced chondrocyte mitophagy through the HCAR2\/AMPK\/PINK1\/Parkin pathway, offering a potential therapeutic approach for the treatment of OA.<\/jats:p>","DOI":"10.1111\/acel.14294","type":"journal-article","created":{"date-parts":[[2024,8,10]],"date-time":"2024-08-10T02:39:39Z","timestamp":1723257579000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["\u03b2\u2010Hydroxybutyrate enhances chondrocyte mitophagy and reduces cartilage degeneration in osteoarthritis via the\n                    <scp>HCAR2<\/scp>\n                    \/\n                    <scp>AMPK<\/scp>\n                    \/\n                    <scp>PINK1<\/scp>\n                    \/Parkin pathway"],"prefix":"10.1111","volume":"23","author":[{"given":"Huangming","family":"Zhuang","sequence":"first","affiliation":[{"name":"Department of Orthopedics Renmin Hospital of Wuhan University  Wuhan 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