{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T05:04:14Z","timestamp":1789535054998,"version":"build-2803163510"},"reference-count":76,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Parkinson\u2019s disease (PD) is a progressive neurodegenerative disorder whose pathogenesis involves complex interactions between metabolic dysfunction and neuroinflammation. The role of cuproptosis, a newly defined copper-dependent cell death pathway that is triggered during mitochondrial aerobic respiration, in PD remains incompletely understood. In this study, we employed integrated bioinformatics on bulk and single-cell RNA sequencing datasets to identify four hub cuproptosis-associated genes (\n                    <jats:italic>DLD<\/jats:italic>\n                    ,\n                    <jats:italic>ULK2<\/jats:italic>\n                    ,\n                    <jats:italic>CCL8<\/jats:italic>\n                    , and\n                    <jats:italic>CCS<\/jats:italic>\n                    ) strongly linked to PD. Functional enrichment and immune infiltration analyses linked these genes to metabolic disturbances and altered immune landscapes in PD. Single-cell transcriptomics further revealed patterns of cell-type-specific expression of these genes and altered inferred intercellular communication, particularly through the NRG signaling pathway between microglia and astrocytes. Experimental validation in AAV9-A53T \u03b1-synuclein mouse models, utilizing cell-type-specific multiplex immunofluorescence (mIF) and western blot analysis, provided supportive evidence for reduced DLD levels in dopaminergic neurons, decreased ULK2 and CCL8 expression in microglia, and diminished CCS content in astrocytes, accompanied by increased FDX1 expression in these cell populations. These findings suggest that dysregulation of cuproptosis-associated hub genes is associated with cell-type-specific pathological alterations in PD, rather than demonstrating a direct causal or synergistic regulatory mechanism. Moreover, in silico drug\u2013target interaction analysis identified four potential therapeutic compounds targeting these hub gene-related proteins. Our findings indicate a potential association between cuproptosis-associated gene dysregulation and metabolic\u2013immune abnormalities in PD, providing candidate biomarkers and possible intervention targets for further validation.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1813166","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T04:30:07Z","timestamp":1789533007000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Cuproptosis-associated genes DLD, ULK2, CCL8, and CCS link metabolic and immunological dysfunction in Parkinson\u2019s disease: a multi-omics study"],"prefix":"10.3389","volume":"17","author":[{"given":"Jing","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Neurology and Department of Neuroscience, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University","place":["Xiamen, China"]},{"name":"Xiamen Key Laboratory of Brain Center","place":["Xiamen, China"]},{"name":"Xiamen Medical Quality Control Center for Neurology","place":["Xiamen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-Hui","family":"Hu","sequence":"additional","affiliation":[{"name":"Xiamen Key Laboratory of Brain Center","place":["Xiamen, China"]},{"name":"Department of Neurosurgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University","place":["Xiamen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Radiology, Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University","place":["Xiamen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurology and Department of Neuroscience, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University","place":["Xiamen, China"]},{"name":"Xiamen Key Laboratory of Brain Center","place":["Xiamen, China"]},{"name":"Xiamen Medical Quality Control Center for Neurology","place":["Xiamen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Dan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology and Department of Neuroscience, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University","place":["Xiamen, China"]},{"name":"Xiamen Key Laboratory of Brain Center","place":["Xiamen, China"]},{"name":"Xiamen Medical Quality Control Center for Neurology","place":["Xiamen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun-Mu","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Neurology and Department of Neuroscience, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University","place":["Xiamen, China"]},{"name":"Xiamen Key Laboratory of Brain Center","place":["Xiamen, China"]},{"name":"Xiamen Medical Quality Control Center for Neurology","place":["Xiamen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nai-An","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Neurology and Department of Neuroscience, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University","place":["Xiamen, China"]},{"name":"Department of Neurology, The Third Hospital of Xiamen","place":["Xiamen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Xi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, Tongji Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Neurology and Department of Neuroscience, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University","place":["Xiamen, China"]},{"name":"Xiamen Key Laboratory of Brain Center","place":["Xiamen, China"]},{"name":"Xiamen Medical Quality Control Center for Neurology","place":["Xiamen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(23)01419-8","article-title":"The epidemiology of Parkinson's disease","volume":"403","author":"Ben-Shlomo","year":"2024","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-022-00684-6","article-title":"Inflammation and immune dysfunction in Parkinson 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