ABSTRACT
The absence of effective therapeutic targets poses considerable obstacles to the treatment of triple-negative breast cancer (TNBC). This study aimed to explore the function and mechanism of polysaccharides derived from the aerial parts of Tetrastigma hemsleyanum (THP) for the treatment of TNBC. THP exerts notable anti-TNBC effects when used alone, and its combination with Doxorubicin (DOX) effectively augments the sensitivity of TNBC cells to DOX. Through RNA sequencing, Fe2+ assays, western blotting, and transmission electron microscopy, THP was identified as a natural inducer of ferroptosis and ferritinophagy through the xCT/GSH/GPX4 and Nrf2/NCOA4/FTH1 pathways. Further research revealed that the THP branched-chain hexose directly binds to the xCT protein to inhibit its expression and promotes ferroptosis. In vivo experiments confirmed the role of THP in inducing ferroptosis and showed that THP improves the tumor microenvironment and immune function by increasing the ratio of CD4+ and CD8+ T cells to regulatory T cells and modulating cytokine levels. As demonstrated by electrocardiography, blood chemistry, and histological analyses, THP alleviates organ toxicity caused by DOX. Overall, these results suggest that THP has significant clinical potential as a natural macromolecular drug and may provide a safe and effective treatment strategy for TNBC when combined with DOX.
