Advances in Redox Research · Oct 29, 2026
Modulation of ferroptosis by different forms of exercise training: A review of the mechanisms and therapeutic implications
By Kargarfard M, Kordi N, Kheirandish R et al.
This review examines how different modalities of exercise training modulate iron homeostasis and antioxidant defense mechanisms involved in the regulation of ferroptosis. Ferroptosis is an iron-dependent form of programmed cell death driven by iron overload, excessive reactive oxygen species, and lipid peroxidation, contributing to metabolic, cardiovascular, and neurodegenerative diseases. Aerobic exercise regulates systemic and cellular iron metabolism, reduces ferritin accumulation, and enhances antioxidant capacity. Evidence indicates activation of the NRF2-SLC7A11 axis, promoting cystine uptake and glutathione (GSH) synthesis, thereby strengthening resistance to lipid peroxidation. Investigations into resistance training have been predominantly oriented toward iron-related and inflammatory markers (specifically hepcidin and ferritin) yet no extant study has directly examined ferroptosis-specific endpoints. High-intensity interval training (HIIT), documented largely through preclinical research in cardiac and metabolic contexts, has demonstrated the potential to modulate iron handling mechanisms and augment GPX4 and SLC7A11 gene expression. Collectively, these exercise modalities appear to modulate iron homeostasis, enhance endogenous antioxidant systems, and may attenuate ferroptosis-related processes. However, most evidence derives from preclinical studies and primarily reflects changes in iron-related markers (e.g., hepcidin, ferritin, and ferroportin) rather than direct ferroptosis markers (e.g., GPX4 activity, lipid peroxidation products, or SLC7A11 protein levels). These findings highlight exercise as a promising non-pharmacological strategy to mitigate ferroptosis-associated cellular injury. Preliminary, large preclinical evidence suggests therapeutic potential in nonalcoholic fatty liver disease, heart failure and neurodegeneration through improved antioxidant defense, reduced iron overload, and decreased lipid peroxidation. Nevertheless, well-designed human studies directly measuring ferroptosis markers are needed to confirm clinical relevance. Overall, exercise-induced regulation of iron metabolism and redox balance provides a promising framework for future research on preventing ferroptosis-related diseases.