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An excess of free metal ions can be pathological and contribute to cell death, but only copper and zinc strongly promote protein aggregation. Herein we demonstrate that the endogenous copper-binding tripeptide glycyl-l-histidyl-l-lysine (GHK) has the ability to bind to and reduce copper redox activity and to prevent copper- and zinc-induced cell death in vitro. In addition, GHK prevents copper- and zinc-induced bovine serum albumin aggregation and reverses aggregation through resolubilizing the protein. We further demonstrate the enhanced toxicity of copper during inflammation and the ability of GHK to attenuate this toxicity. Finally, we investigated the effects of copper on enhancing paraquat toxicity and report a protective effect of GHK. We therefore conclude that GHK has potential as a cytoprotective compound with regard to copper and zinc toxicity, with positive effects on protein solubility and aggregation that warrant further investigation in the treatment of neurodegenerative diseases.<\/jats:p>","DOI":"10.1093\/mtomcs\/mfae019","type":"journal-article","created":{"date-parts":[[2024,4,11]],"date-time":"2024-04-11T00:25:48Z","timestamp":1712795148000},"source":"Crossref","is-referenced-by-count":11,"title":["Glycyl-<scp>l<\/scp>-histidyl-<scp>l<\/scp>-lysine prevents copper- and zinc-induced protein aggregation and central nervous system cell death <i>in vitro<\/i>"],"prefix":"10.1093","volume":"16","author":[{"given":"Jin-Hong","family":"Min","sequence":"first","affiliation":[{"name":"Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital , S-171 76 Stockholm , Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heela","family":"Sarlus","sequence":"additional","affiliation":[{"name":"Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital , S-171 76 Stockholm , Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert A","family":"Harris","sequence":"additional","affiliation":[{"name":"Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital , S-171 76 Stockholm , Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,4,10]]},"reference":[{"issue":"2","key":"2024052912310528900_bib1","doi-asserted-by":"crossref","first-page":"678","DOI":"10.3390\/ijms23020678","article-title":"Mechanistic insights expatiating the redox-active-metal-mediated neuronal degeneration in Parkinson's disease","volume":"23","author":"Behl","year":"2022","journal-title":"Int. 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