Targeting Ferroptosis as a New Approach for Radiation Protection and Mitigation

Abstract: Radiation-induced normal cell toxicity (RINCT) is a major factor to consider while treating any ailment with radiotherapy. Clinical irradiation of tumors necessitates an understanding of the potential efficacy of radiation protective agents in reducing radiation damage to healthy tissues and their effects on tumor tissue radiosensitivity. Ferroptosis is a relatively new form of iron-dependent cell death that has been linked to a variety of disease pathologies. The key mediators of ferroptosis have been identified as lipid peroxidation and iron metabolism. Lipid peroxidation is the result of a reaction between reactive oxygen (ROS) and reactive nitrogen species (RNS) with phosphatidylethanolamine-containing polyunsaturated fatty acids (PUFAs). Ferroptosis inhibitors have been demonstrated to have anti-inflammatory effects in animal models of disease. It was recently shown that ionizing radiation (IR) generates severe ferroptosis, a critical component of RT-mediated normal cell toxicity. These findings support the use of ferroptosis inhibitor treatments for the treatment of radiation normal cell toxicity. Targeting lipid metabolic substrates and controlling ferroptosis by radiation could reduce toxicity and improve clinical outcomes. In this study, we address the relationships between radiotherapy and various types of radiation-induced cell death, and we discuss the interactions between ferroptosis and other kinds of controlled cell death generated by radiotherapy, and we investigate combination treatment options targeting ferroptosis in radiotherapy. This review will be a foundation for future research on ferroptosis in radiotherapy. Additionally, the relevant patents on ferroptosis inhibitors with various therapeutic potentials have been discussed.