Targeting
ferritin via autophagy (ferritinophagy) to induce ferroptosis, an
iron- and
reactive oxygen species (ROS)-dependent cell death, provides novel strategies for
cancer therapy. Using a ferroptosis-specific inhibitor and
iron chelator, the vulnerability of
triple-negative breast cancer (TNBC) MDA-MB-231 cells to ferroptosis was identified and compared to that of
luminal A MCF-7 cells.
Saponin formosanin C (FC) was revealed as a potent ferroptosis inducer characterized by superior induction in cytosolic and
lipid ROS formation as well as GPX4 depletion in MDA-MB-231 cells. The FC-induced ferroptosis was paralleled by downregulation of
ferroportin and xCT expressions. Immunoprecipitation and electron microscopy demonstrated the involvement of ferritinophagy in FC-treated MDA-MB-231 cells. The association of FC with ferroptosis was strengthened by the results that observed an enriched pathway with differentially expressed genes from FC-treated cells. FC sensitized
cisplatin-induced ferroptosis in MDA-MB-231 cells. Through integrated analysis of differentially expressed genes and pathways using the METABRIC patients' database, we confirmed that autophagy and ferroptosis were discrepant between TNBC and
luminal A and that TNBC was hypersensitive to ferroptosis. Our data suggest a therapeutic strategy by ferroptosis against TNBC, an aggressive subtype with a poor prognosis.