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The osteogenesis of periodontal ligament stem cells (PDLSCs) plays a pivotal role in maintaining alveolar bone homeostasis. In this study, we found that dysregulated lipid metabolism induces ferroptosis and mitochondrial dysfunction in PDLSCs, impairing their osteogenic differentiation and exacerbating alveolar bone loss in both in vitro and in vivo models. Mechanistically, free fatty acids activate glycogen synthase kinase 3 beta (GSK3\u03b2), which facilitates Kelch\u2010like ECH\u2010associated protein 1 (KEAP1)\u2010independent, beta\u2010transducin repeat\u2010containing protein (\u03b2\u2010TrCP)\u2010mediated ubiquitin\u2013proteasome degradation of nuclear factor erythroid 2\u2010related factor 2 (NRF2). This leads to reduced expression of key antioxidant enzymes such as Glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), resulting in redox imbalance and ferroptosis of PDLSCs. Notably, pharmacological inhibition of either GSK3\u03b2 or ferroptosis restores NRF2 stability, alleviates oxidative stress, and rescues the osteogenic potential of PDLSCs. Furthermore, local inhibition of GSK3\u03b2 significantly attenuates alveolar bone destruction in a hyperlipidemia\u2010associated periodontitis mouse model. Collectively, our findings identify a novel GSK3\u03b2\u2013NRF2\u2013ferroptosis pathway that mediates the detrimental effects of hyperlipidemia on PDLSC function and periodontal homeostasis, offering a promising therapeutic target for metabolic disorder\u2010associated periodontal damage.<\/jats:p>","DOI":"10.1002\/advs.75157","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T19:35:02Z","timestamp":1775590502000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Hyperlipidemia Aggravates Alveolar Bone Loss via Periodontal Ligament Stem Cell Ferroptosis Through GSK3\u03b2 Dependent Ubiquitin\u2010Mediated NRF2 Degradation"],"prefix":"10.1002","volume":"13","author":[{"given":"Yuxiao","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Stomatology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan 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