Ferroptosis is an iron-dependent form of regulated cell death driven by excessive lipid peroxidation and reactive oxygen species (ROS) accumulation. Herein, we report a novel metal-coordinated nanoparticle system (OFe-NPs) fabricated via a one-pot self-assembly between orlistat and FeCl3·6 H₂O for ferroptosis-based tumor therapy. The optimized OFe-NPs exhibited uniform nanoscale size and good colloidal stability under physiological conditions. In MCF-7 breast cancer cells, OFe-NPs showed significantly enhanced cytotoxicity compared with free orlistat, which was attributed to glutathione (GSH)-responsive disassembly and intracellular release of Fe ions and orlistat. Mechanistic investigations revealed that OFe-NPs effectively induced ferroptosis, as evidenced by increased lipid peroxidation, intracellular Fe2+ accumulation, glutathione depletion, malondialdehyde elevation, and marked downregulation of GPX4. In an MCF-7 xenograft mouse model, OFe-NPs treatment significantly suppressed tumor growth, achieving a tumor inhibition rate of 76.76% with no evident systemic toxicity. These findings demonstrate that metal-coordinated orlistat–Fe(III) nanoparticles synergistically amplify ferroptosis via simultaneous iron-mediated oxidative stress and GPX4 suppression, offering a promising strategy for cancer therapy.
Ren et al. (Sun,) studied this question.