{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:41:24Z","timestamp":1791232884854,"version":"4.1.0"},"reference-count":24,"publisher":"Wiley","issue":"21","license":[{"start":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T00:00:00Z","timestamp":1762992000000},"content-version":"vor","delay-in-days":12,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T00:00:00Z","timestamp":1761955200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100005088","name":"Beijing Municipal Health Commission","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005088","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Wilson disease (WD) is an inherited disorder caused by ATP7B mutations, resulting in toxic copper accumulation primarily in the liver and brain. While copper\u2010induced hepatotoxicity is a hallmark of WD, the mechanisms linking copper overload to liver injury remain unclear. This study aimed to investigate the role of cuproptosis, a copper\u2010dependent form of regulated cell death, in WD pathogenesis and identify key cuproptosis\u2010related genes (CRGs). We utilised ATP7B\u2212\/\u2212 mice and HepG2 cells to model WD. Liver injury was assessed histologically and biochemically. Transcriptomic analysis identified differentially expressed CRGs, followed by machine learning (LASSO, SVM\u2010RFE) to identify key genes. Functional enrichment and protein validation were performed. Candidate biomarkers were evaluated in WD patient serum and confirmed in the mouse model. ATP7B\u2212\/\u2212 mice showed marked hepatocellular injury with elevated AST, ALT and LDH. Cuproptosis markers (FDX1, DLST, DLAT, LIAS) were upregulated in both liver tissue and HepG2 cells. Copper exposure decreased cell viability and increased LDH release, exacerbated by Elesclomol and alleviated by Tetrathiomolybdate. Transcriptomics revealed Lox, App, Afp, Alb, Gpc1, Gls were central hub genes. Importantly, SiRNA knockdown of Gpc1, Gls, Lox and App alleviated cuproptosis, supporting their key roles in cuproptosis. Cuproptosis plays a critical role in copper\u2010induced liver injury in WD. Key mediators identified include Gpc1, Gls, Lox and App, which were validated as potential therapeutic targets. These findings provide new insights into the molecular mechanisms underlying WD and may inform the development of targeted treatment strategies.<\/jats:p>","DOI":"10.1111\/jcmm.70946","type":"journal-article","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T12:41:51Z","timestamp":1763037711000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Uncovering the Critical Role of Cuproptosis in Wilson Disease: Insights Into Potential Therapeutic Targets"],"prefix":"10.1111","volume":"29","author":[{"given":"Shan","family":"Tang","sequence":"first","affiliation":[{"name":"First Department of Hepatology, Beijing Youan Hospital Capital Medical University  Beijing China"},{"name":"Beijing Institute of Hepatology\/Beijing Youan Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Ren","sequence":"additional","affiliation":[{"name":"Beijing Institute of Hepatology\/Beijing Youan Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Hou","sequence":"additional","affiliation":[{"name":"First Department of Hepatology, Beijing Youan Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihao","family":"Fan","sequence":"additional","affiliation":[{"name":"Beijing Institute of Hepatology\/Beijing Youan Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinkang","family":"Mo","sequence":"additional","affiliation":[{"name":"Beijing Institute of Hepatology\/Beijing Youan Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianru","family":"Zhu","sequence":"additional","affiliation":[{"name":"Beijing Institute of Hepatology\/Beijing Youan Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaling","family":"Cao","sequence":"additional","affiliation":[{"name":"Beijing Institute of Hepatology\/Beijing Youan Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Xu","sequence":"additional","affiliation":[{"name":"Beijing Institute of Hepatology\/Beijing Youan Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8228-2819","authenticated-orcid":false,"given":"Sujun","family":"Zheng","sequence":"additional","affiliation":[{"name":"First Department of Hepatology, Beijing Youan Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,13]]},"reference":[{"key":"e_1_2_10_2_1","first-page":"221","article-title":"Wilson Disease: Novel Diagnostic and Therapeutic Approaches","volume":"45","author":"Marino Z.","year":"2024","journal-title":"Seminars in Liver Disease"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.2174\/1574888X16666211006111556"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijns11010006"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/HC9.0000000000000150"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11894-018-0660-7"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2011.11.007"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.847436"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12883-019-1502-4"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abf0529"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-022-00653-7"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-022-01014-x"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2003.05.010"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/liv.14646"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI45401"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1353111"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-018-0018-3"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25094753"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000040598"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.70282"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-030420-105050"},{"issue":"7","key":"e_1_2_10_22_1","first-page":"607","article-title":"Hippo Signaling Pathway in Liver Tissue Homeostasis","volume":"39","author":"Li Y. 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