Abstract

Oxidative stress is increasingly recognized as a key contributor to the pathophysiology of periodontitis, particularly in patients with metabolic disturbances such as hyperlipidemia. 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 (GSK3β), which facilitates Kelch-like ECH-associated protein 1 (KEAP1)-independent, beta-transducin repeat-containing protein (β-TrCP)-mediated ubiquitin–proteasome degradation of nuclear factor erythroid 2-related 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 GSK3β or ferroptosis restores NRF2 stability, alleviates oxidative stress, and rescues the osteogenic potential of PDLSCs. Furthermore, local inhibition of GSK3β significantly attenuates alveolar bone destruction in a hyperlipidemia-associated periodontitis mouse model. Collectively, our findings identify a novel GSK3β–NRF2–ferroptosis pathway that mediates the detrimental effects of hyperlipidemia on PDLSC function and periodontal homeostasis, offering a promising therapeutic target for metabolic disorder-associated periodontal damage.