Platycodin D2 Mediates Incomplete Autophagy and Ferroptosis in Breast Cancer Cells by Regulating Mitochondrial ROS

ABSTRACT Platycodin D2 (PD2) is a triterpenoid saponin extracted from the root of Platycodon grandiflorum , a common source of medicine and food. Platycodon grandiflorum saponins have anti‐inflammatory, antioxidative, antitumor, and immunity‐promoting effects. However, the effect of PD2 on breast cancer cells has not been reported. The purpose of this study is to explore the molecular mechanism underlying the effect of PD2 on breast cancer cells. We analyzed the inhibitory effects and pathways of PD2 on breast cancer by CCK‐8 assay, WB assay, and immunofluorescence assay. Subsequently, autophagy and ferroptosis were analyzed using different inhibitors. It was found that PD2 caused mitochondrial damage and promoted mitochondrial reactive oxygen species (mtROS) production, leading to autophagy flux inhibition and ferroptosis. Blockage of autophagy flux and ferroptosis promoted each other, resulting in the inhibition of breast cancer cell proliferation. Similar results were obtained in the tumor‐bearing model in vivo. PD2 promoted autophagy flux blockage and ferroptosis in breast cancer cells, which induced each other under the action of mtROS, thus inhibiting the proliferation of breast cancer cells. PD2 is a potential new strategy for the treatment of breast cancer.