Bruceine A Ameliorates Osteoporosis Through Suppression of <scp>RACK1</scp> ‐Mediated Osteoclastogenesis

Bruceine A (BA) is a quassinoid compound derived from Brucea javanica with various pharmacological activities. Our previous work has revealed that BA exhibits anti-inflammatory and glucose-lowering effects in db/db mice, resulting in significant protection against diabetic kidney disease. However, considering the pivotal role of inflammatory signaling pathways during osteoclast differentiation, whether and how BA exerts protection against osteoporosis remains to be explored. In the present work, we have demonstrated that BA exhibits significant protective efficacy against bone loss in ovariectomized and diabetic mice, which mimic postmenopausal and diabetic osteoporosis, respectively. Moreover, BA is found to attenuate RANKL-induced osteoclast differentiation and function in isolated bone marrow-derived macrophages and the RAW264.7 cell line at non-cytotoxic concentrations. Mechanistically, BA binds to RACK1 to disrupt the RACK1-c-SRC interaction, thereby suppressing the inflammatory signaling pathways involved in regulating osteoclastogenesis in a RACK1-dependent manner. Altogether, our findings establish BA as a novel therapeutic agent for treating osteoporosis.