Ziyuglycoside II suppressed the progression of osteosarcoma by coordinating estrogen-related receptor gamma and p53 signaling pathway

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. Despite ongoing efforts, the 5-year survival rate has not shown significant improvement over many years, underscoring the urgent need for the development of novel drugs to enhance current treatment protocols. Ziyuglycoside Ⅱ (ZYG Ⅱ), a triterpenoid saponin extracted from S. officinalis, has recently been found to exhibit antitumor activity. This study evaluated the antitumor effect of ZYG II on osteosarcoma and identified its mechanism of action through the co-regulation of p53 and ESRRG, which inhibits the progression of the disease. This research utilized in vitro experiments with multiple commonly used osteosarcoma cell lines, as well as in vivo studies employing a nude mouse model of orthotopic xenograft osteosarcoma. Besides, ESRRG shRNA was employed to construct stable ESRRG-reducing OS cell lines to elucidate the molecular mechanism by which ZYG Ⅱ exerts its anti-osteosarcoma effects through the co-regulation of ESRRG and p53. The results indicate that administration of ZYG Ⅱ led to a decrease of viability of OS cells and a reduced of tumor volumes. In addition, cell cycles were arrested at the G₀/G₁ phase, while the proportions of apoptotic cells increased. Furthermore, expression of p53, ESRRG, p21, Bax, Cleaved Caspase-9 and Cleaved Caspase-3 proteins were increased and expression of CDK4, Cyclin D1 and Bcl-2 proteins were reduced. Multiple ZYG Ⅱ and ESRRG docking patterns were simulated by molecular docking. By comparing the pharmacodynamic response of ZYG Ⅱ to OS cell lines with reduced ESRRG and normal expression, it was demonstrated that ZYG Ⅱ inhibits the progression of osteosarcoma, leads to cell cycle arrest and promotes cell apoptosis through coordinating of p53 and ESRRG. In conclusion, ZYG Ⅱ inhibits the progression of osteosarcoma, leads to cell cycle arrest and promotes cell apoptosis through synergistic regulation of p53 and ESRRG.