["Journal of Cellular Physiology, Volume 241, Issue 4, April 2026. ", "Rh3R disrupts the c‐Fos/NFATc1 axis, thereby inhibiting RANKL‐induced osteoclastogenesis and functional podosome belt assembly without affecting osteoblast activity.\n\n\n\n\n\n\nABSTRACT\nThe homeostatic balance of bone remodeling is governed by the precise coordination between bone‐forming osteoblasts and bone‐resorbing osteoclasts. In this study, we investigated the anti‐resorptive properties of rhamnocitrin‐3‐rhamnoside (Rh3R), a flavonoid isolated from Loranthus tanakae, using primary bone marrow‐derived macrophages (BMMs) and calvaria‐derived osteogenic progenitor cells (COCs) to ensure biological relevance. Our findings demonstrate that Rh3R potently inhibits the RANKL‐induced differentiation of BMMs into TRAP‐positive multinucleated osteoclasts in a dose‐dependent manner, without inducing cytotoxicity. Mechanistically, Rh3R effectively attenuates RANKL‐induced downstream signaling cascades, as evidenced by the attenuated phosphorylation of MAPKs (ERK1/2, JNK, p38), AKT, and IκB. This signaling blockade subsequently suppresses the induction of the master transcription factors, c‐Fos and NFATc1. Furthermore, Rh3R impairs the functional resorptive capacity of mature osteoclasts by destabilizing F‐actin‐rich ring structures accompanied by decreased integrin β3 expression, thereby preventing the formation of a functional sealing zone. The inhibitory effect of Rh3R on bone‐degrading activity was further confirmed by a significant reduction in the total area of resorption pits on bone slices. Notably, Rh3R exhibits a lineage‐specific inhibitory effect, showing no adverse influence on osteoblastogenesis or the mineralizing capacity of primary osteogenic cells. Furthermore, the effect of Rh3R was consistently maintained in a co‐culture system of primary osteoblasts and BMMs. Collectively, these in vitro findings identify Rh3R as a bioactive modulator of osteoclast differentiation and function via suppression of RANKL‐induced downstream signaling, warranting future in vivo and pharmacological studies to evaluate efficacy, exposure, and safety."]