Hexahydrocurcumin inhibits osteoclastogenesis and bone destruction in osteoporosis by targeting c-Src

Osteoporosis is a chronic disorder marked by bone wasting and increased bone fragility. Targeted inhibition of osteoclastogensis is currently the core therapeutic strategy. Hexahydrocurcumin (HHC), derived from Zingiberis Rhizoma, has been shown to exhibit anti-inflammatory and antioxidant properties; however, its effects on osteoclasts regulation and osteoporosis pathogenesis remain unexplored. We conducted this study to observe the influence of HHC on RANKL-mediated osteoclast precursor differentiation and OVX-dependent osteoporotic mice. In this study, we revealed that HHC significantly attenuated the generation and bone resorptive function of osteoclasts induced by RANKL in vitro, which was achieved by targeting and inhibiting the phosphorylation of c-Src, a critical molecule in osteoclast differentiation. Next, HHC inhibited the subsequent Ca²⁺ influx and NFATc1 nuclear translocation, thereby suppressing the expression of osteoclastogenic regulators such as Acp5 and Mmp9. Furthermore, we validated that HHC inhibits osteoclastogenesis by targeting c-Src through siRNA-mediated silencing of c-Src. In the in vivo study, HHC notably alleviated bone loss in OVX-dependent osteoporotic mice. These findings suggest that HHC alleviates osteoporosis by inhibiting osteoclastogenesis via targeting c-Src, which provide preliminary evidence for the potential of HHC for the treatment of osteoporosis.