<scp>SZQ</scp> ‐3, a Novel Synthetic Chromone‐Maleimide Hybrid Targeting <scp>NF</scp> ‐ <scp>κB</scp> , Prevents Postmenopausal Osteoporosis by Modulating Mitochondrial Function in Bone Cells

The therapeutic utility of current anti-osteoporotic drugs is limited owing to adverse effects and safety concerns, highlighting the urgent need for safer and more effective alternatives. SZQ-3, a chromone-maleimide hybrid, exhibits anti-inflammatory and antioxidant properties. However, the efficacy of SZQ-3 against osteoporosis and the underlying mechanisms remain unexplored. In the study, we assessed the protective effects of SZQ-3 on osteoblasts and inhibitory effects on osteoclast differentiation, and its ability to prevent PMOP progression. In vitro, osteoblast apoptosis and osteoclast differentiation were evaluated using H₂O₂-stimulated MC3T3-E1 cells and RANKL-induced RAW264.7 cells, respectively. RNA sequencing, molecular docking, and pathway analyses were employed to elucidate mechanisms. In vivo efficacy and safety were assessed in an ovariectomy-induced estrogen deficiency-related bone loss mouse model. Our results indicated that SZQ-3 suppressed H₂O₂-induced osteoblast apoptosis and inhibited receptor activator of nuclear factor-kappa B ligand (RANKL)-stimulated osteoclast differentiation. Transciptomic analysis identified nuclear factor kappa B (NF-κB) signaling as a key regulatory pathway. Molecular docking revealed a strong binding affinity of SZQ-3 to NF-κB, involving specific hydrogen bond interactions. SZQ-3 attenuated H₂O₂- and RANKL-induced activation of the NF-κB pathway by reducing phosphorylation and impeding nuclear translocation of NF-κB, stabilizing mitochondrial function. In ovariectomized mice, SZQ-3 exhibited significant anti-osteoporotic efficacy with an excellent safety profile. These findings suggest SZQ-3 is a potent NF-κB inhibitor and a strong dual-action therapeutic agent against osteoporosis and lay the groundwork for future clinical development.