Orthodontic tooth movement (OTM) relies on bone remodeling, but sustained compression often compromises osteoblast viability, leading to bone loss. This study investigates how the mechanosensitive channel Piezo1 mediates force-induced osteoblast ferroptosis.

Using a rat OTM model and compressed MC-3T3-E1 cells, we modulated Piezo1 and NFATc1 using lentiviral and pharmacological tools (GsMTx4, NFATc1-IN, Yoda1). Bone microarchitecture (Micro-CT), lipid peroxidation (C11-BODIPY), and markers (GPX4, ALP, OPN) were assessed.

Compressive force hyperactivates Piezo1, triggering Ca²⁺ influx and NFATc1 nuclear translocation. Nuclear NFATc1 transcriptionally represses the antioxidant enzyme GPX4, leading to lipid peroxidation and ferroptosis. While Piezo1 is required for basal osteogenesis, its overactivation under pressure drives cell death. Pharmacological inhibition of NFATc1 or GPX4 overexpression attenuated ferroptosis and significantly restored bone formation and trabecular microarchitecture under loading.

The Piezo1-NFATc1-GPX4 axis is a critical "mechanotransduction-to-death" pathway under sustained compression. Targeting NFATc1-mediated ferroptosis presents a novel strategy to preserve osteoblast integrity and enhance alveolar bone regeneration during mechanical loading.(This research was funded by the National Key Research and Development Program of China (No.2023YFC2506300) and Jiangsu Funding Program for Excellent Postdoctoral Talent (2025ZB538)).