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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>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\u2013glutathione 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\u2013body 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.<\/jats:p>","DOI":"10.3390\/ijms27156628","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T09:47:41Z","timestamp":1785145661000},"page":"6628","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exercise and Ferroptosis in Neurodegenerative Diseases: Direct Evidence, Mechanistic Links, and Translational Gaps"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-6782-8941","authenticated-orcid":false,"given":"Mengzhao","family":"Han","sequence":"first","affiliation":[{"name":"College of Education and Sports Sciences, Yangtze University, Jingzhou 434023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoran","family":"Huang","sequence":"additional","affiliation":[{"name":"College of Education and Sports Sciences, Yangtze University, Jingzhou 434023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3708-9830","authenticated-orcid":false,"given":"Xinguo","family":"Yuan","sequence":"additional","affiliation":[{"name":"College of Education and Sports Sciences, Yangtze University, Jingzhou 434023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5350-3848","authenticated-orcid":false,"given":"Penglei","family":"Fan","sequence":"additional","affiliation":[{"name":"College of Education and Sports Sciences, Yangtze University, Jingzhou 434023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3553-6932","authenticated-orcid":false,"given":"Ming","family":"Li","sequence":"additional","affiliation":[{"name":"College of Education and Sports Sciences, Yangtze University, Jingzhou 434023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"a028035","DOI":"10.1101\/cshperspect.a028035","article-title":"Pathology of Neurodegenerative Diseases","volume":"9","author":"Dugger","year":"2017","journal-title":"Cold Spring Harb. 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