Paris saponin VII suppresses osteosarcoma progression by targeting VEGFR2 and PD-L1 to enhance anti-angiogenic and immunotherapeutic efficacy.

objectiveTo investigate the inhibitory effects and underlying mechanisms of Paris saponin VII (PS VII) on osteosarcoma (OS) progression.

methodsHuman osteosarcoma MG63 cells were treated with PS VII at concentrations of 0, 1, and 10 µmol·L⁻¹. Cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay, and clonogenic capacity was evaluated by colony formation assays. Potential molecular targets of PS VII were predicted using the SwissTargetPrediction database. Intersection targets between PS VII-related targets and OS differentially expressed genes (DEGs) were identified, followed by protein–protein interaction (PPI) network construction to screen core targets. Molecular docking was performed to validate compound–target interactions. Western blotting was used to verify the regulatory effects of PS VII on key protein targets. In vivo, a K7M2 murine osteosarcoma subcutaneous xenograft model was established to evaluate tumor growth and therapeutic synergy with bevacizumab or anti-PD-1 antibody.

resultsCompared with the control group (0 µmol·L⁻¹), treatment with 1 and 10 µmol·L⁻¹ PS VII significantly reduced MG63 cell viability and colony-forming ability (P < 0.05). Both Rhizoma Paridis extract and PS VII (10 mg·kg⁻¹) markedly inhibited the growth of K7M2 subcutaneous tumors (P < 0.05). A total of 47 potential therapeutic targets of PS VII against OS were identified, which were closely associated with the IL-17 signaling pathway, Rap1 signaling pathway, and related oncogenic pathways. Core targets included EGFR, AKT1, MMP9, KDR (VEGFR2), and CD274 (PD-L1). Molecular docking analysis demonstrated strong binding affinities between PS VII and CD274, KDR, and EGFR. Western blot analysis revealed that PS VII significantly downregulated VEGFR2 and PD-L1 protein expression (P < 0.01). Immunohistochemical analysis showed that PS VII markedly reduced CD31⁺ microvessel density and increased CD8⁺ T-cell infiltration (P < 0.01). Compared with controls, combination treatment with PS VII plus bevacizumab or PS VII plus anti-PD-1 antibody significantly slowed tumor growth and reduced tumor volume.

conclusionParis saponin VII suppresses osteosarcoma cell proliferation and tumor progression, potentially through downregulation of VEGFR2 and PD-L1, thereby enhancing the efficacy of anti-angiogenic and immunotherapeutic strategies.