Aerobic Exercise-Mediated Regulation of Ferroptosis in Skeletal Disorders: Molecular Mechanisms and Potential...

Skeletal disorders, including osteoporosis, osteoarthritis, rheumatoid arthritis, and osteonecrosis of the femoral head, are common chronic conditions that substantially affect health and quality of life. Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, has increasingly been implicated in abnormal bone remodeling, cartilage degeneration, synovial pathology, and impaired skeletal homeostasis. Aerobic exercise is an important non-pharmacological approach for maintaining skeletal health, but the role of ferroptosis in its protective effects remains incompletely understood. Previous reviews have mainly discussed ferroptosis in skeletal disorders or the beneficial effects of exercise on skeletal health as separate topics. In contrast, this review places aerobic exercise, ferroptosis, and skeletal disorders within a unified framework and summarizes current evidence across osteoporosis, osteoarthritis, rheumatoid arthritis, and osteonecrosis of the femoral head. We further discuss how aerobic exercise may influence ferroptosis through the regulation of iron homeostasis, lipid peroxidation, antioxidant defense, and inflammatory responses, with attention to recently emerging molecular evidence and to the distinction between direct findings from bone- and joint-related tissues and supportive evidence from non-skeletal systems. Current direct evidence is concentrated mainly in osteoblast-related bone loss and osteoarthritis and is derived predominantly from animal and cellular studies, whereas direct clinical evidence in humans remains limited. Overall, available evidence supports ferroptosis as a potential mechanistic link between aerobic exercise and skeletal protection, but its role in mediating exercise-induced benefits in humans has yet to be established. Further clinical validation of this relationship may help clarify the biological basis of aerobic exercise interventions and support the development of more targeted exercise strategies for the prevention and management of skeletal disorders.