ABSTRACT: Osteoclast fusion is a critical step for bone resorption, and its dysregulation contributes to pathological bone loss such as postmenopausal osteoporosis. Siglec15, a membrane-bound lectin, has emerged as a key regulator of osteoclast precursor recognition and fusion. Here, we report that Cajanin, a natural small-molecule compound, effectively inhibits osteoclastogenesis and bone resorption both in vitro and in vivo. Cajanin treatment suppressed actin ring formation, bone resorptive activity, and the expression of osteoclastic markers including Ctsk, Mmp9, and c-Fos in a dose-dependent manner. Transcriptomic profiling revealed that Cajanin downregulated key fusion mediators such as Siglec15, DC-STAMP, OC-STAMP, and NFATc1. Gene enrichment analysis identified attenuated MAPK and NFκB signaling, which was validated by decreased phosphorylation of ERK, JNK, and p38, increased IκBα levels, and reduced nuclear translocation of p65. Moreover, Cajanin significantly suppressed NFATc1 expression and nuclear localization. In an ovariectomy-induced bone loss model, Cajanin preserved trabecular bone architecture and reduced TRAP-positive osteoclasts. Collectively, our findings demonstrate that Cajanin transcriptionally disrupts the Siglec15–NFATc1 signaling axis, thereby impairing osteoclast fusion and bone resorption, and highlight its potential as a therapeutic candidate for selectively targeting pathological osteoclast fusion in osteolytic diseases.
