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Glycophagy\u2014a process of glycogen-selective autophagy that degrades intracellular glycogen into glucose\u2014is essential for maintaining glucose homeostasis under metabolic stress. The role of glycophagy in regulating M1-type polarization remains unclear. In this study, we found that M1-type polarization correlated with increased glycophagy in a diabetic mandibular bone defect model. Proteomic analysis revealed the involvement of the glycophagy mediator acid \u03b1-glucosidase (GAA) in M1-type polarization in diabetic bone callus. Mechanistically, the upregulation of GAA drove M1-type polarization to inhibit osteogenesis under high-glucose conditions by activating the mTORC1 signaling pathway. Transplant of GAA-silenced macrophages restored the osteogenic capability in mandibular injury in diabetic rats. In conclusion, our study unravels the regulation of a fundamental mechanism of M1-type polarization by the glycophagy mediator GAA, providing insights relevant for promoting bone generation in diabetic individuals.<\/jats:p>","DOI":"10.1177\/00220345251350658","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T05:34:29Z","timestamp":1757482469000},"page":"374-384","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Acid \u03b1-Glucosidase Impairs Diabetic Bone Regeneration via Altering Macrophage Polarization"],"prefix":"10.1177","volume":"105","author":[{"given":"S.C.","family":"Yu","sequence":"first","affiliation":[{"name":"Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi\u2019an Jiaotong University, Xi\u2019an, China"},{"name":"Department of Periodontology, College of Stomatology, Xi\u2019an Jiaotong University, 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