NCOA4 as a regulatory switch linking DNA damage to lipid peroxidation in radiation response

Radiotherapy remains a cornerstone of cancer treatment; however, radioresistance and normal tissue toxicity continue to limit its therapeutic efficacy. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as an important determinant of radiation response and a promising target for radiosensitization. Among the regulatory mechanisms involved, NCOA4-mediated ferritinophagy has attracted increasing attention because it controls intracellular iron mobilization through selective ferritin degradation. Nevertheless, its role should be considered within the broader regulatory network governing radiation-induced ferroptosis. This review summarizes current evidence on the interplay between radiotherapy, iron metabolism, and ferroptosis, with emphasis on the regulatory contribution of NCOA4-mediated ferritinophagy. We discuss how radiation-induced DNA damage responses, oxidative stress, autophagy-lysosome pathways, and the tumor microenvironment collectively influence iron homeostasis and ferroptosis susceptibility. We further integrate recent advances in lipid remodeling, antioxidant defense systems, and the spatiotemporal dynamics of intracellular iron redistribution following irradiation. In addition, the interactions between ferroptosis and other radiation-induced cell death programs are highlighted to provide a comprehensive perspective on radiation-induced cellular responses. Finally, we critically evaluate the therapeutic potential and current limitations of targeting NCOA4-mediated ferritinophagy for radiosensitization. Rather than functioning as the sole determinant of radiation-induced ferroptosis, NCOA4 represents an important regulatory component within an integrated network of iron metabolism, oxidative stress, and lipid peroxidation. A better understanding of these interconnected mechanisms may facilitate the development of more effective and selective ferroptosis-based radiotherapeutic strategies.