<scp>HIF</scp> ‐1α/ <scp>HO</scp> ‐1 Axis Promotes Ferroptosis and Impairs Periodontal Tissue Repair in Periodontitis

ABSTRACT Aim To investigate whether the hypoxia‐inducible factor‐1alpha (HIF‐1α)/heme oxygenase‐1 (HO‐1) axis mediates ferroptosis in periodontal ligament tissues and contributes to impaired periodontal tissue repair in periodontitis. Materials and Methods RNA sequencing was performed to identify ferroptosis‐related pathways in ligature‐induced periodontitis (LIP) model. In vivo, LIP and ligature‐removal recovery models were treated with the ferroptosis inhibitor Ferrostatin‐1 (Fer‐1). Alveolar bone changes were assessed by micro‐computed tomography. Osteoclast activity and periodontal ligament–associated repair were evaluated by TRAP staining and Periostin immunohistochemistry. Ferroptosis‐related alterations were assessed by immunohistochemistry of HIF‐1α, HO‐1, GPX4, SLC7A11, 4‐HNE and Perls staining. In vitro, an HIF‐1α‐activated hPDLSC model was established. Ferroptosis‐related changes were evaluated by ROS, MDA, Fe 2+ levels, C11‐BODIPY staining and expression of ferroptosis‐associated molecules. The HIF‐1α/HO‐1 regulatory relationship was examined by ChIP‐qPCR and dual‐luciferase reporter assays. Results RNA sequencing revealed enrichment of ferroptosis‐related pathways and identified HIF‐1α and HO‐1 as central regulators in inflamed periodontal ligament tissues. In vivo, Fer‐1 attenuated alveolar bone loss, osteoclast activity and inflammatory cell infiltration. These changes were accompanied by decreased HO‐1 expression, iron deposition and 4‐HNE levels, along with increased GPX4 and SLC7A11 expression. In the recovery model, Fer‐1 further reduced oxidative stress, suppressed osteoclast activity and increased Periostin expression, indicating improved periodontal tissue repair. In vitro, HIF‐1α activation was associated with increased Fe 2+ accumulation, ROS production and ferroptosis‐related molecular alterations. Mechanistically, HIF‐1α directly transactivated HO‐1, which contributed to iron accumulation and downstream ferroptosis‐associated changes. Conclusions The HIF‐1α/HO‐1 signalling axis is associated with ferroptosis‐related alterations in the PDL, which constitute periodontal tissue damage and impaired repair in periodontitis.