A natural protopanaxatriol from Panax notoginseng enhances osteosarcoma sensitivity to ferroptosis via ASCL4 upregulation

• (20S)-Protopanaxatriol (PPT), a natural product from Panax notoginseng , enhances osteosarcoma cell sensitivity to ferroptosis. • (20S)-PPT increases ACSL4 expression, a key enzyme that promotes lipid peroxidation, thereby sensitizing osteosarcoma cells to ferroptosis inducers like RSL3. • The combination of (20S)-PPT and IKE significantly suppresses osteosarcoma xenograft growth in vivo . • Targeting ACSL4 with (20S)-PPT presents a promising therapeutic approach for osteosarcoma, especially in cases resistant to conventional chemotherapy. Current treatments for osteosarcoma, the most common primary bone cancer, including surgery, radiotherapy, and chemotherapy, are largely ineffective against metastatic and chemo-resistant cases, emphasizing the need for novel therapies. In this study, we investigated (20S)-Protopanaxatriol [(20S)-PPT], a natural product from Panax notoginseng, an herb used both as food and medicine, for its ability to enhance osteosarcoma sensitivity to ferroptosis induced by inducers such as RSL3, ML210, and IKE. Specifically, (20S)-PPT increased lipid peroxidation in osteosarcoma cells exposed to RSL3. This effect was mediated by ACSL4 upregulation, as ACSL4 knockdown reversed (20S)-PPT-sensitized ferroptosis. Importantly, (20S)-PPT significantly reduced tumor growth in xenograft models when combined with IKE. Collectively, our study confirms that combining (20S)-PPT with ferroptosis inducers offers a promising novel strategy for treating osteosarcoma.