Radiotherapy-induced oxidative stress and mitochondrial dysfunction: potential contributions of toxic elements and associated biomarkers—a systematic review

Abstract

Radiotherapy is a cornerstone of cancer treatment; however, radiation-induced injury to normal tissues remains an important limitation. Ionizing radiation generates reactive oxygen species (ROS) through direct and indirect mechanisms, including water radiolysis, thereby contributing to oxidative stress, mitochondrial dysfunction, inflammation, and normal-tissue injury. This systematic review synthesizes clinical and experimental evidence concerning the molecular mechanisms of radiotherapy-induced oxidative and mitochondrial injury, with particular attention to the potential modifying role of toxic-element exposure and associated biomarkers. The available clinical and experimental evidence on radiotherapy-induced oxidative stress, mitochondrial dysfunction, and the potential contribution of toxic-element exposure was systematically reviewed. Particular consideration was given to lead (Pb), cadmium (Cd), arsenic (As), mercury (Hg), chromium (Cr), nickel (Ni), and aluminum (Al), as well as biomarkers of oxidative, antioxidant, mitochondrial, and cellular stress. The potential utility of inductively coupled plasma mass spectrometry (ICP-MS) for quantifying toxic-element burden was also evaluated. Experimental and limited clinical evidence suggests that exposure to Pb, Cd, As, Hg, Cr, Ni, and Al may alter antioxidant defenses, redox homeostasis, and mitochondrial function and could therefore influence cellular responses to radiotherapy. However, direct clinical evidence demonstrating that toxic-element burden independently or synergistically increases radiotherapy toxicity remains limited. Malondialdehyde (MDA), catalase (CAT), and glutathione peroxidase (GPx) provide complementary information regarding lipid peroxidation and antioxidant defense, whereas growth differentiation factor-15 (GDF-15) represents a broader stress-responsive marker that may reflect mitochondrial and cellular stress but is not radiation-specific. ICP-MS provides sensitive multi-element quantification and may facilitate investigation of toxic-element burden in patients receiving radiotherapy. The evidence supports an integrated mechanistic framework linking radiation-induced oxidative stress, mitochondrial dysfunction, inflammatory signaling, and potential toxic-element-related susceptibility. Nevertheless, the proposed toxic-element “double-hit” model remains a testable hypothesis rather than a clinically validated phenomenon. Prospective longitudinal studies integrating toxic-element measurements, oxidative and mitochondrial biomarkers, radiation dosimetry, and clinically defined toxicity outcomes are required to establish its clinical relevance.