摘要Osteosarcoma(OS)is the most prevalent primary malignant bone tumor affecting children and adolescents.Despite ongoing research efforts,the 5-year survival rate has remained stag-nant for many years,highlighting the critical need for novel drug development to enhance current treatment protocols.Ziyuglycoside Ⅱ(ZYG Ⅱ),a triterpenoid saponin extracted from S.officinalis,has recently demonstrated antitumor properties.This study evaluates the antitu-mor effect of ZYG Ⅱ on osteosarcoma and elucidates its mechanism of action through the co-regulation of p53 and estrogen-related receptor gamma(ESRRG),which inhibits disease pro-gression.The research employs in vitro experiments using multiple established osteosarcoma cell lines,as well as in vivo studies utilizing a nude mouse model of orthotopic xenograft os-teosarcoma.Additionally,ESRRG shRNA was used to construct stable ESRRG-reducing OS cell lines to investigate the molecular mechanism by which ZYG Ⅱ exerts its anti-osteosarcoma ef-fects through the co-regulation of ESRRG and p53.Results indicate that ZYG Ⅱ administration led to decreased OS cell viability and reduced tumor volumes.Furthermore,cell cycles were arrested at the G0/G1 phase,while the proportion of apoptotic cells increased.Expression of p53,ESRRG,p21,Bax,Cleaved Caspase-9,and Cleaved Caspase-3 proteins increased,while expression of CDK4,Cyclin D1,and Bcl-2 proteins decreased.Multiple ZYG Ⅱ and ESRRG dock-ing patterns were simulated through molecular docking.Comparing the pharmacodynamic re-sponse of ZYG Ⅱ to OS cell lines with reduced ESRRG and normal expression demonstrated that ZYG Ⅱ inhibits osteosarcoma progression,induces cell cycle arrest,and promotes cell ap-optosis through the coordination of p53 and ESRRG.In conclusion,ZYG Ⅱ inhibits osteosar-coma progression,leads to cell cycle arrest,and promotes cell apoptosis through synergistic regulation of p53 and ESRRG.