Exercise and Ferroptosis in Neurodegenerative Diseases: Direct Evidence, Mechanistic Links, and Translational Gaps

Ferroptosis is an iron-dependent form of regulated cell death characterized by iron dyshomeostasis, glutathione depletion, glutathione peroxidase 4 dysfunction, and excessive lipid peroxidation. Exercise is a safe and accessible non-pharmacological intervention with broad neuroprotective potential, but the evidentiary basis linking exercise specifically to ferroptosis is uneven. Only a limited subset of studies directly combines an exercise intervention with ferroptosis-related outcomes in neurodegenerative models; much of the proposed pathway architecture is inferred from pharmacological, cellular, observational, or acute neurological injury studies. This review therefore separates direct exercise evidence from exercise-related supporting evidence and non-exercise mechanistic evidence. The most directly relevant findings, concentrated largely in aerobic exercise models, show exercise-associated changes in brain iron handling, the cystine/glutamate antiporter-glutathione peroxidase 4 antioxidant system, and lipoxygenase-dependent lipid peroxidation. Supporting studies suggest additional peripheral-to-central mechanisms involving muscle-derived exosomes, exercise-associated changes in systemic and cerebral iron handling, and inflammatory regulation. Bone marrow hematopoiesis, adult neurogenesis, synaptic plasticity, and astrocyte-controlled iron traffic are incorporated as biologically plausible but incompletely tested links. Evidence for resistance training, high-intensity interval training, mind-body exercise, and human disease remains insufficient. The central limitation is therefore not pathway plausibility but the scarcity of exercise-specific causal experiments demonstrating that ferroptosis suppression is required for neuroprotection.