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Disruptions in their metabolism and regulatory pathways have been associated with the pathogenesis of various forms of neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD). Despite growing research on metal homeostasis, the intricate molecular mechanisms that link iron and copper metabolism to the initiation and progression of NDDs remain insufficiently elucidated. In this review, we provide a systematic overview of the metabolic processes of iron and copper in the body and CNS, highlighting their interactions with many metal\u2010binding proteins, including transporters, storage proteins, and important intrinsically disordered proteins (e.g., amyloid \u03b2\u2010protein, tau, and alpha\u2010synuclein) involved in NDDs. We further dissect the downstream effects of metal ion dyshomeostasis on cellular redox balance, neuroinflammation, autophagy, organelle interaction network, and cell death. Additionally, we discuss current therapeutic strategies aimed at targeting iron and copper dyshomeostasis, as well as the emerging role of artificial intelligence in this field of research. By integrating metal metabolism, metal\u2013protein interactions, the effect of metal dyshomeostasis on downstream biological processes, and potential intervention strategies, this review serves as a comprehensive reference for understanding the pathogenesis of NDDs and offers new perspectives for developing effective therapeutics. Overall, this review underscores the significance of reinstating metal balance for the treatment of neurodegeneration.<\/jats:p>","DOI":"10.1002\/mco2.70766","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T03:56:03Z","timestamp":1779162963000},"source":"Crossref","is-referenced-by-count":0,"title":["Exploring and Targeting the Connection of Iron and Copper Homeostasis to Neurodegenerative Diseases"],"prefix":"10.1002","volume":"7","author":[{"given":"Xin","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Geriatrics, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University)  Shenzhen 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