SZQ ‐3, a Novel Synthetic Chromone‐Maleimide Hybrid Targeting NF ‐ κB , 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.