The novel Nrf2 agonist neobavaisoflavone attenuates periodontitis by inhibiting osteoclastogenesis through iron homeostasis regulation and senescence suppression.

Abstract

BACKGROUND: Overactivation of osteoclasts plays a key driver of bone loss in osteolytic diseases, including periodontitis. Although current antiresorptive agents are clinically effective, their long-term safety and economic burden limit widespread use, highlighting the need for novel, mechanism-based therapeutic strategies. OBJECTIVE: This study aims to evaluate the impact of the natural flavonoid neobavaisoflavone (NBIF), on osteoclast function and periodontitis progression, and explore its underlying molecular mechanisms. METHODS: In vitro, osteoclast differentiation and resorptive activity were assessed using TRAP staining, F-actin ring formation, and scanning electron microscopy. Mechanistic studies employed transcriptomic analysis, molecular docking, and cellular thermal shift assays (CETSA). The therapeutic efficacy and safety of NBIF were further evaluated in a ligature-induced periodontitis mouse model. RESULTS: NBIF markedly inhibited osteoclast differentiation, F-actin ring formation, and bone resorption in vitro. Mechanistic investigations revealed that NBIF directly binds Keap1, stabilizes Nrf2, and promotes its nuclear translocation, leading to upregulation of the iron exporter FPN1, reduction of intracellular iron levels, and suppression of ferroptosis signaling and senescence. In vivo, NBIF significantly mitigated alveolar bone loss, improved trabecular bone architecture, and exhibited favorable safety profiles. CONCLUSION: NBIF shows strong therapeutic potential for osteolytic diseases by suppressing osteoclast formation and bone resorption through the KEAP1-NRF2-FPN1 axis, highlighting the iron metabolism-senescence pathway as a promising therapeutic target and providing a new paradigm for drug development in osteoclast-related bone loss.