Radiation-Induced Lipid Peroxidation Triggers Ferroptosis and Synergizes with Ferroptosis Inducers

Inhibition or GPX4 inhibition synergize with radiation to induce ferroptosis in several cancer types by enhancing cytoplasmic lipid peroxidation but not increasing DNA damage or caspase activation. Ferroptosis inducers synergized with cytoplasmic irradiation, but not nuclear irradiation. Finally, administration of ferroptosis inducers enhanced the antitumor effect of radiation in a murine xenograft model and in human patient-derived models of lung adenocarcinoma and glioma. These results suggest that ferroptosis inducers may be effective radiosensitizers that can expand the efficacy and range of indications for radiation therapy.

• NI
  National Institutes of Health

  Award: 1S10OD010631-01A1
• NC
  National Cancer Institute

  Awards: R35CA209896, P01CA087497-17, P30CA013696
• NI
  National Institute of Neurological Disorders and Stroke

  Award: R61NS109407
• NI
  National Institute of Biomedical Imaging and Bioengineering

  Award: 5P41EB002033