Chrysoeriol: a natural RANKL inhibitor targeting osteoclastogenesis and ROS regulation for osteoporosis therapy.

Chrysoeriol (CHE) is a naturally occurring compound with established anti-inflammatory and anti-tumor effects. This study examines its potential role in regulating osteoclast differentiation and activity, both of which are crucial for bone remodeling. Computational docking revealed high binding affinity between CHE and RANKL, specifically at the Lys-181 residue of RANKL, suggesting potential inhibitory interactions on osteoclastogenesis. In vitro assays confirmed CHE's non-toxic profile at concentrations below 20 μM and demonstrated a dose-dependent suppression of osteoclast differentiation. Notably, CHE treatment significantly reduced TRAP activity and bone resorption capacity in a dose-dependent manner. Furthermore, CHE markedly decreased ROS production by NOX-1 expression and modulated the NRF2/KEAP1 pathway to enhance ROS clearance. The compound also showed inhibitory effects on the NF-κB and MAPK signaling pathways, which are crucial for osteoclast activation. In an ovariectomized mouse model, administration of CHE mitigated bone loss, indicating its therapeutic potential in osteoporosis. Collectively, these findings establish CHE as a promising natural therapeutic agent for treating bone disorders characterized by excessive bone resorption, underscoring the need for further clinical investigation.