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

ACS Chem Biol. 2020 Feb 21;15(2):469-484. doi: 10.1021/acschembio.9b00939. Epub 2020 Jan 14.


Although radiation is widely used to treat cancers, resistance mechanisms often develop and involve activation of DNA repair and inhibition of apoptosis. Therefore, compounds that sensitize cancer cells to radiation via alternative cell death pathways are valuable. We report here that ferroptosis, a form of nonapoptotic cell death driven by lipid peroxidation, is partly responsible for radiation-induced cancer cell death. Moreover, we found that small molecules activating ferroptosis through system xc- 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Transport System y+ / metabolism
  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Carbolines / therapeutic use
  • Cell Line, Tumor
  • Ferroptosis / drug effects*
  • Gamma Rays
  • Humans
  • Imidazoles / therapeutic use
  • Ketones / therapeutic use
  • Lipid Peroxidation / drug effects
  • Lipid Peroxidation / radiation effects*
  • Mice, Nude
  • Neoplasms / drug therapy*
  • Neoplasms / radiotherapy*
  • Piperazines / therapeutic use
  • Radiation-Sensitizing Agents / therapeutic use*
  • Sorafenib / therapeutic use
  • Xenograft Model Antitumor Assays


  • Amino Acid Transport System y+
  • Antineoplastic Agents
  • Carbolines
  • Imidazoles
  • Ketones
  • Piperazines
  • RSL3 compound
  • Radiation-Sensitizing Agents
  • SLC7A11 protein, human
  • imidazole ketone erastin
  • Sorafenib