摘要Osteoporosis,the most prevalent skeletal disorder,is primarily driven by aberrantly increased osteoclast formation and/or activity.Targeting hyperactive osteoclasts remains the cornerstone of current thera-peutic strategies.Crebanine(Cre),a natural isoquinoline-derived alkaloid with diverse pharmacological activities,has not yet been explored for osteoporosis treatment.This study aimed to evaluate the therapeutic potential of Cre against ovariectomy(OVX)-induced osteoporosis and elucidate its under-lying mechanisms.Cre dose-dependently inhibited in vitro osteoclast differentiation,actin ring for-mation,and bone resorption by downregulating nuclear factor of activated T cells 1(NFATc1)and key osteoclast-related genes.Simultaneously,Cre enhanced osteoblast differentiation and mineralization,upregulated osteoblast marker genes,and restored hydrogen peroxide-impaired alkaline phosphatase(ALP)activity impaired by hydrogen peroxide,indicating dual regulation of bone remodeling.Mecha-nistically,Cre activated sirtuin 1(Sirt1),promoting p65 deacetylation,inactivated IκB kinase(IKK),and stabilized IκBα,thus inhibiting nuclear factor-kappaB(NF-κB)signaling.Additionally,Cre reduced reactive oxygen species(ROS)by upregulating antioxidant enzymes(heme oxygenase-1(HO-1),cata-lase)and suppressing nicotinamide adenine dinucleotide(NAD)phosphate(NADPH)oxidases(NOX1/4).Furthermore,Cre specifically bound to the predicted site of receptor activator of NF-κB(RANK),blocking RANK ligand(RANKL)-RANK interaction and disrupting downstream protein kinase B(Akt)and mitogen-activated protein kinase(MAPK)signaling pathways.In the OVX mouse model,Cre signifi-cantly attenuated bone loss and osteoclastogenesis.Crucially,Cre showed no toxicity in liver or kidney function tests.Collectively,these findings demonstrate that Cre exerts dual therapeutic effects,inhib-iting osteoclastogenesis via Sirt1-mediated NF-κB/ROS suppression and promoting osteoblast activity,providing a promising therapeutic strategy for osteoporosis.