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Osteosarcoma is a malignant tumor abundant in vascular tissue, and its rich blood supply may have a significant impact on its metabolic characteristics. PDGFRβ is a membrane receptor highly expressed in osteosarcoma cells and vascular wall cells, and its effect on osteosarcoma metabolism needs to be further studied. In this study, we discussed the effect and mechanism of action of PDGFRβ on glucose metabolism in human osteosarcoma (HOS) cells. GSEA, Pearson's correlation test, and PPI correlation analysis indicated positive regulation of PDGFRβ on aerobic glycolysis in osteosarcoma. The results of qPCR and western blot further confirmed the prediction of bioinformatics. Glucose metabolism experiments proved that PDGF/PDGFRβ could effectively promote aerobic glycolysis in osteosarcoma cells. In addition, the mitochondrial membrane potential (ΔΨm) experiment proved that the metabolic change triggered by PDGFRβ was not caused by mitochondrial damage. The PI3K pathway inhibitor LY294002, MEK pathway inhibitor U0126, or Warburg effect inhibitor DCA was used to perform western blot and glucose metabolism experiments, and the results showed that PDGFBB/PDGFRβ mainly activated the PI3K/AKT/mTOR/c-Myc pathway to promote aerobic glycolysis in osteosarcoma HOS cells. The newly elucidated role of PDGFRβ provides a novel metabolic therapeutic target for osteosarcoma. [ABSTRACT FROM AUTHOR]