Targeting ferroptosis and ferritinophagy improves tooth extraction socket healing in type 2 diabetes mellitus via...

Delayed tooth extraction socket (TES) healing is a significant complication in patients with poorly controlled type 2 diabetes mellitus (T2DM). Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has been implicated in various T2DM-induced pathologies; however, its role in TES healing remains unclear. This study aimed to investigate the mechanisms of ferroptosis induced by a high-glucose environment in T2DM, focusing on its effects on human bone marrow mesenchymal stem cells (HBMSCs), iron content, and ferritinophagy. Additionally, we evaluate the therapeutic potential of a chitosan (CS) hydrogel delivery system loaded with Dl-3-n-butylphthalide (NBP) and black phosphorus (BP) nanoparticles (NBP@BP@CS) in promoting TES healing under diabetic conditions. Our findings demonstrate that ferroptosis is activated in the alveolar bone of T2DM rats, contributing to delayed TES healing. In vitro, high glucose and palmitic acid impaired osteogenesis and induced ferroptosis in HBMSCs. Both in vivo and in vitro experiments revealed that nuclear receptor coactivator 4 knockdown and treatment with iron chelators (deferoxamine and 3-methyladenine) alleviated ferroptosis and osteogenic impairment, highlighting ferritinophagy (autophagic degradation of ferritin) as a key driver of T2DM-induced ferroptosis. Furthermore, the NBP@BP@CS hydrogel demonstrated potent reactive oxygen species scavenging properties, significantly accelerating TES healing in T2DM. These findings showed ferritinophagy-dependent ferroptosis as a novel mechanism underlying delayed TES healing in T2DM and proposed NBP@BP@CS as a promising therapeutic strategy for diabetes-associated complications.