Tectorigenin Ameliorates Glucocorticoid‐Induced Osteoporosis by Inhibiting the <scp>NF</scp>‐<scp>κB</scp> Signal Pathway and Modulating Treg‐Th17 Cell Balance

Glucocorticoid-induced osteoporosis is a common clinical orthopaedic disease, primarily due to excessive use of hormones. Tectorigenin has shown a certain efficacy in treating osteoporosis, but its underlying mechanisms are not yet fully understood. This study aimed to evaluate tectorigenin (TEC)'s potential in treating glucocorticoid-induced osteoporosis (GIOP) by restoring the osteoclast-osteoblast balance. By employing molecular docking to study TEC-RANKL interaction and RNA sequencing to map TEC's anti-osteoporotic pathways, we conducted in vitro tests on TEC's effects on osteoclast differentiation, bone resorption, ROS production, and NF-κB activation. We performed a luciferase reporter assay for Nrf2 and NF-κB activities and evaluated TEC's in vivo efficacy using a GIOP mouse model with micro-CT and histomorphometric analyses, measuring serum RANKL levels and Treg/Th17 cell ratios. Docking analysis confirmed TEC's specific binding to RANKL and RNA sequencing showed TEC modulated osteoclast pathways. In vitro, TEC suppressed osteoclastogenesis, bone resorption, osteoclast gene expression, and ROS activity by downregulating NFATc1 and modulating NF-κB. The luciferase assay revealed TEC inhibited Nrf2 and influenced its interaction with NF-κB. In vivo, TEC protected against GIOP by balancing Th17/Treg cells to inhibit osteoclast differentiation and maintain bone volume. In conclusion, tectorigenin (TEC) shows promise in reducing osteoclastogenesis and preventing GIOP, making it a potential drug candidate for osteoporosis management.