Ferroptosis Inhibits Cementoblast Mineralization Via Cgas-Sting/Gpx4 Axis

To investigate the role of the cGAS-STING/GPX4 axis in ferroptosis and its impact on cementoblast mineralization under compressive force, and its involvement in orthodontically induced inflammatory external root resorption (OIIERR). The murine cementoblast cell line OCCM-30 was subjected to a 2 g/cm² compressive force for 24 hours to establish an in vitro model.Western blot analyzed mineralization-related proteins (RUNX2, OPN, OCN) and cGAS-STING/GPX4 axis proteins. Ferroptosis was evaluated by measuring ROS, Fe2+, and MDA levels. Mitochondrial damage was examined via mitochondrial membrane potential (MMP) analysis and mtDNA linkage evaluation. To further investigate the role of cGAS-STING/GPX4 axis-mediated ferroptosis, STING knockdown and Ferrostatin-1 (Fer-1) were utilized. In vivo, an OIIERR mouse model was established, and the STING inhibitor H-151 was administered to assess the involvement of cGAS-STING/GPX4 axis-mediated ferroptosis in OIIERR. Compressive force significantly reduced RUNX2, OPN, OCN, and GPX4 levels while increasing ROS, Fe²⁺, and MDA levels. MMP reduction and mtDNA leakage into the cytoplasm were observed. cGAS-STING pathway proteins (cGAS, p-STING, p-TBK1, p-IRF3) were upregulated under compressive force. Knockdown of STING or Fer-1 treatment restored cementoblast mineralization. In vivo, H-151 administration reduced cGAS-STING/GPX4 activation and mitigated root resorption. The cGAS-STING/GPX4 axis mediates ferroptosis, impairing cementoblast mineralization under compressive force, and contributes to OIIERR. Targeting this pathway, as demonstrated with H-151, offers a potential therapeutic approach for OIIERR management.