Synthetic Vectors for Activating the Driving Axis of Ferroptosis

Ferroptosis is a promising strategy for cancer therapy, with numerous inhibitors of its braking axes under investigation as potential drugs. However, few studies have explored the potential of activating the driving axes to induce ferroptosis. Herein, phosphatidylcholine peroxide decorating liposomes (LIPPCPO) were synthesized to induce ferroptosis by targeting divalent metal transporter 1 (DMT1). LIPPCPO was found to boost lysosomal Fe2+ efflux by inducing cysteinylation of lysosomal DMT1, resulting in glutathione peroxidase 4 (GPX4) suppression, glutathione depletion and ferroptosis in breast cancer cells and xenografts. Importantly, LIPPCPO induced ferroptotic cell death was independent of acquired resistance to radiation, chemotherapy, or targeted agents in 11 cancer cell lines. Furthermore, a strong synergistic ferroptosis effect was observed between LIPPCPO and an FDA-approved drug, artesunate. The formula of LIPPCPO encapsulating artesunate significantly inhibited tumor growth and metastasis and improved the survival rate of breast cancer-bearing mice. These findings provide a distinct strategy for inducing ferroptosis and highlight the potential of LIPPCPO as a vector to synergize the therapeutic effects of conventional ferroptosis inducers.