Radiotherapy-induced oxidative stress and mitochondrial dysfunction: potential contributions of toxic elements and associated biomarkers—a systematic review
- 1Department of Pharmacology and Toxicology, Qassim University
- 2Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine for Girls, Al-Azhar University
Abstract
Introduction: 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.
Methods: 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.
Results: 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.
Discussion and Conclusion: 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.
Related
- Identification and validation of biomarkers associated with mitochondrial dynamics dysfunction in Parkinson’s disease based on GEO datasets
- Mitochondrial Dysfunction in Diabetic Neuropathy: An Evidence Map of Molecular Mechanisms, Translational Biomarkers, and Emerging Implications for Oral Neuropathy-A Scoping Review.
- Sepsis-associated endothelial dysfunction: clinical phenotypes, biomarkers, bedside evidence, and translational implications
- Inflammation-Related Biomarkers Linking Environmental Chemical Mixtures and Metabolic Dysfunction-Associated Steatotic Liver Disease: A Population-Based Study from NHANES 1999-2020
- Human embryonic stem cell-derived mesenchymal stem cells ameliorate mitochondrial oxidative dysfunction in metabolic dysfunction-associated steatotic liver disease.
BibTeX
@article{alharkan2026radiotherapyinduced,
title = {{Radiotherapy-induced oxidative stress and mitochondrial dysfunction: potential contributions of toxic elements and associated biomarkers—a systematic review}},
author = {Amjad Ahmed Saleh Alharkan and Ashraf Mahmoud Emara and Samia Soliman Barghash},
journal = {Frontiers in Public Health},
year = {2026},
month = oct,
doi = {10.3389/fpubh.2026.1969155},
url = {https://www.frontiersin.org/articles/10.3389/fpubh.2026.1969155/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Radiotherapy-induced oxidative stress and mitochondrial dysfunction: potential contributions of toxic elements and associated biomarkers—a systematic review
AU - Amjad Ahmed Saleh Alharkan
AU - Ashraf Mahmoud Emara
AU - Samia Soliman Barghash
PY - 2026
DA - 2026/10/14
JO - Frontiers in Public Health
DO - 10.3389/fpubh.2026.1969155
UR - https://www.frontiersin.org/articles/10.3389/fpubh.2026.1969155/full
AB - Introduction: 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. Methods: 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. Results: 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. Discussion and Conclusion: 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.
SN - 2296-2565
ER -