Ionizing Radiation in Clinical Diagnostics and Radiotherapy: The Dual Role of NRF2 in Cell Protection and Carcinogenesis

Ionizing radiations (IRs), commonly used in both diagnostic imaging and cancer therapy, generate reactive oxygen species (ROS) and free radicals, causing significant DNA damage that can lead to genetic mutations, cell death, and tissue injury in both normal and tumor tissues. In response to the oxidative stress, the nuclear factor erythroid 2-related factor 2 (NRF2) is activated to induce target genes involved in antioxidant and detoxifying pathways, thereby playing a pivotal role in protecting cells from IR-induced oxidative damage. In clinical diagnostics, IR exposure from imaging techniques can result in DNA damage, inflammation, and increased risk of IR-induced pathologies, including cancer. NRF2 activation in response to these diagnostic exposures can help to protect normal tissues from damage by boosting antioxidant defenses. In radiotherapy, IR induces DNA damage to kill malignant cells, although it may also harm surrounding healthy tissue. Cancer cells exploit NRF2 activation to resist IR-induced cell damage, thereby maintaining redox balance and protecting themselves from oxidative stress. In that case, NRF2 inhibition could sensitize cancer cells to IR effects by disrupting their antioxidant defense, leading to increased ROS accumulation, enhanced DNA damage, and greater cell death. This review will summarize the role of NRF2 in mediating the response to IR in both healthy and cancerous cells, with a focus on its effects in clinical diagnostic and radiotherapy.