摘要This study investigated the regulatory potential of salidroside(SAL),a primary active com-pound in Rhodiola rosea L.,on osteoclast differentiation by modulating the hypoxia-inducible factor 1-alpha(HIF-1α)pathway in osteoblasts.Luciferase reporter assay and chromatin im-munoprecipitation(ChIP)assay were employed to validate whether the receptor activator of nuclear factor-κB ligand(RANKL)is the downstream target gene of HIF-1α in osteoblasts.The study also utilized lipopolysaccharide(LPS)-induced mouse osteolysis to examine the impact of SAL on osteolysis in vivo.Furthermore,conditioned medium(CM)from SAL-pretreated os-teoblasts was used to investigate the paracrine effects on osteoclastogenesis through the HIF-1α pathway.Hypoxic condition-induced overexpression of HIF-1α upregulated RANKL levels by binding to the RANKL promoter and enhancing transcription in osteoblastic cells.In vivo,SAL significantly alleviated bone tissue hypoxia and decreased the expression of HIF-1α by downregulating the expression of RANKL,vascular endothelial growth factor(VEGF),inter-leukin 6(IL-6),and angiopoietin-like 4(ANGPTL4).In the paracrine experiment,conditioned media from SAL-pretreated osteoblasts inhibited differentiation through the HIF-1α/RANKL,VEGF,IL-6,and ANGPTL4 pathways.RANKL emerges as the downstream target gene regu-lated by HIF-1α in osteoblasts.SAL significantly alleviates bone tissue hypoxia and bone loss in LPS-induced osteolysis through the HIF-1α/RANKL,VEGF,IL-6,and ANGPTL4 pathways.SAL inhibits osteoclast differentiation by regulating osteoblast paracrine secretion.