Ferroptosis in Radiation-Induced Ovarian Injury: Molecular Mechanisms and Emerging Therapeutic Strategies

Abstract

Radiation therapy is one of the most common treatments for cancer. However, side effects on normal tissues remain a major clinical concern. The ovary is highly radiosensitive, and ionizing radiation (IR) can impair ovarian function and fertility by inducing oxidative stress, mitochondrial dysfunction, and multiple forms of cell death, ultimately leading to follicular depletion. Ferroptosis is an iron-dependent form of regulated cell death characterized by lipid peroxidation and has recently emerged as a potential contributor to IR-induced ovarian injury. IR can induce ferroptosis by disrupting iron homeostasis, impairing the System Xc−–GSH–GPX4 antioxidant defense pathway, and promoting lipid peroxidation. Recent preclinical studies have shown ferroptosis-related alterations in irradiated ovarian tissue and granulosa cells. In parallel, IR activates the well-established TAp63–PUMA/NOXA apoptotic pathway in oocytes, highlighting the involvement of multiple cell death mechanisms in ovarian injury. Nevertheless, targeting ferroptosis may help reduce granulosa cell injury and mitigate certain aspects of ovarian damage. This review evaluates current evidence for ferroptosis as one of the cell death mechanisms contributing to IR-induced ovarian injury, with particular emphasis on its molecular mechanisms, interactions with other cell death pathways, and emerging therapeutic strategies. Potential therapeutic strategies include the preservation of GPX4-dependent antioxidant defenses, inhibition of lipid peroxidation, regulation of iron homeostasis, and modulation of polyunsaturated fatty acid-related lipid metabolism. Nevertheless, direct evidence remains limited, and further research is needed to clarify the contribution of ferroptosis to IR-induced ovarian injury and evaluate whether targeting this pathway can mitigate ovarian damage without compromising tumor radiosensitivity.