Hypoxia Delays Tooth Extraction Healing By Hif-1Α-Ezh2 Signaling

These findings provide new insights into bone stabilization under hypoxic conditions and suggest potential clinical interventions for periodontal bone regeneration. Following M2 extraction, IACUC-approved male rats were allocated to Normoxia and Hypoxia (14% O₂) groups. Animals were sacrificed at 2 and 6 weeks post-operation to assess HIF-1α expression/localization and alveolar healing through integrated analysis using Micro-CT, immunohistochemistry, immunofluorescence, and Western blot. In vitro, we observed the effects of continuous hypoxia on osteogenic and osteoclastic differentiation by staining,PCR and Western blot . We also investigated HIF-1α-EZH2 Signaling Pathway in bone remodeling by immunofluorescence, and Western blot. Sustained hypoxia enhanced osteoclast formation while simultaneously suppressing osteogenesis both in vitro and in vivo. Mechanistically, Hypoxia-inducible factor 1α (HIF-1α) overexpression significantly augmented EZH2-mediated activation of the Wnt/β-catenin signaling pathway and promoted RUNX2 expression, thereby orchestrating osteogenic differentiation. In conclusion, our study demonstrated that EZH2 functions as a critical mediator of both osteogenic and osteoclastic differentiation under hypoxic conditions. EZH2 inhibition reversed the suppressive effects of HIF-1α overexpression on osteogenesis by triggering the Wnt/β-catenin pathway and RUNX2 expression. These mechanistic insights not only expand the therapeutic potential of EZH2-targeted interventions but also suggest novel strategies to enhance extraction socket healing.