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<p>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 FeCl<sub>3</sub>·6&#xa0;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 Fe<sup>2+</sup> 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.</p>

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Self-assembled orlistat–Fe(III) nanoparticles amplify ferroptosis for enhanced tumor therapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月19日

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  • Jinxiao Ren,
  • Shiping Li,
  • Juping Shen

摘要

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.