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Irisin, a novel exercise\u2010induced myokine, is involved in the regulation of bone metabolism. However, the effects of irisin on adipose\u2010derived stem cell (ASC) osteogenic differentiation and bone healing under diabetic conditions remain poorly understood. ASCs were obtained from inguinal fat of Sprague\u2010Dawley rats and treated with different concentrations of AGEs and irisin. Cell proliferation, apoptosis, and osteogenic differentiation abilities of ASCs were detected. To explore the regulatory role of sirtuin 3 (SIRT3), ASCs were transfected with lentivirus\u2010mediated SIRT3 overexpression or knockdown vectors. Next, we investigated mitochondrial functions, mitophagy, and mitochondrial biogenesis in different groups. Moreover, SOD2 acetylation and potential signaling pathways were assessed. Additionally, a diabetic rat model was used to evaluate the effect of irisin on bone healing in calvarial critical\u2010sized defects (CSDs) in vivo. Our results showed that irisin incubation mitigated the inhibitory effects of AGEs on ASCs by increasing cell viability and promoting osteogenesis. Moreover, irisin modulated mitochondrial membrane potential, intracellular ROS levels, mitochondrial O<jats:sub>2<\/jats:sub><jats:sup>\u00b7\u2212<\/jats:sup> status, ATP generation, complex I and IV activities, mitophagy, and mitochondrial biogenesis via a SIRT3\u2010mediated pathway under AGEs exposure. Furthermore, in calvarial CSDs of diabetic rats, transplantation of gels encapsulating irisin\u2010pretreated ASCs along with irisin largely enhanced bone healing. These findings suggest that irisin attenuates AGE\u2010induced ASC dysfunction through SIRT3\u2010mediated maintenance of oxidative stress homeostasis and regulation of mitophagy and mitochondrial biogenesis. Thus, our studies shed new light on the role of irisin in promoting the ASC osteogenesis and targeting SIRT3 as a novel therapeutic intervention strategy for bone regeneration under diabetic conditions.<\/jats:p>","DOI":"10.1155\/2022\/3319056","type":"journal-article","created":{"date-parts":[[2022,10,10]],"date-time":"2022-10-10T22:20:47Z","timestamp":1665440447000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Irisin Promotes Osteogenesis by Modulating Oxidative Stress and Mitophagy through SIRT3 Signaling under Diabetic 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