[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-413995-105":59,"doc-detail-413995-en":131},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":124,"head_meta":126,"extra_data":128,"updated_unix":130},105,"en","glioblastoma-stem-cells-resist-cuproptosis-with-circadian-variation-of-copper-levels","Glioblastoma stem cells resist cuproptosis with circadian variation of copper levels","","Glioblastoma (GBM) stem cells exhibit relative resistance to cuproptosis accompanied by circadian fluctuations in intracellular copper levels. CRISPR screening identified ATP7A as a key copper regulator during copper ionophore treatment or clock disruption, while BMAL1 controlled copper homeostasis via the core circadian clock. ATP7A promoted tumor growth by regulating fatty acid desaturation. Copper levels suppressed BMAL1 through p62-mediated lysosomal degradation, forming feedback between copper and circadian circuitry that reshapes lipid metabolism and supports drug resistance.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/glioblastoma-stem-cells-resist-cuproptosis-with-circadian-variation-of-copper-levels/413995/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/glioblastoma-stem-cells-resist-cuproptosis-with-circadian-variation-of-copper-levels/413995.png","ImageObject",300,407,{"name":92,"@type":93},"Patrick","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-04","2026-09-28",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",12,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What is cuproptosis and how is it related to copper in cells?","Question",{"text":113,"@type":114},"Cuproptosis is triggered by accumulation of intracellular copper, which promotes mitochondrial lipoylated protein aggregation and destabilizes iron–sulfur cluster proteins, leading to cell death.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How do glioblastoma stem cells respond to cuproptosis across the circadian cycle?",{"text":118,"@type":114},"GBM stem cells display relative resistance to cuproptosis with circadian variation in intracellular copper levels.",{"name":120,"@type":111,"acceptedAnswer":121},"Which regulators connect the circadian clock to copper homeostasis and tumor growth?",{"text":122,"@type":114},"BMAL1 mediates circadian control of copper homeostasis, and ATP7A supports tumor cell growth through regulation of fatty acid desaturation; copper also feeds back to the clock via p62-mediated lysosomal degradation of BMAL1.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},413995,1790764049,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146,"preview_page_count":4},549758146520,"https://ap-avatar.wpscdn.com/avatar/80002397d8c0411e94?_k=1775819394049821470","The Journal of Clinical Investigation RESEAR CH ARTICLE  \nGlioblastoma stem cells resist cuproptosis with circadian variation of copper levels  \nFanen Yuan,1,2 Xujia Wu,1 Huairui Yuan,1 Donghai Wang,1,3 Tengfei Huang,1,3 Po Zhang,1 Hailong Mi,1,3 Weichi Wu,1,3 Suchet Taori,1 Priscilla Chan,4 Kenji Miki,2 Maged T. Ghoche,2 Linjie Zhao,1 Kalil G. Abdullah,1,2 Steve A. Kay,4 Qiulian Wu,1,3,6 and Jeremy N. Rich1,3,7,8  \n1UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA. 2Department of Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. 3Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA. 4Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. 5Department of Neurosurgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China. 6Department of Medicine and 7Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. 8Department of Neurology, University of North Carolina, Chapel Hill, North Carolina, USA.  \nCuproptosis involves accumulation of intracellular copper that triggers mitochondrial lipoylated protein aggregation and destabilization of iron–sulfur cluster proteins, leading to cell death. Pharmacologic induction of cuproptosis has been proposed as a cancer therapy. Here, we find that glioblastoma (GBM) stem cells (GSCs) displayed relative resistance to cuproptosis with circadian variation of intracellular copper levels. CRISPR screening of copper regulators under concurrent treatment with copper ionophore or clock disruption revealed dependency on ATPase copper transporting alpha (ATP7A) . Circadian control of copper homeostasis was mediated by the core clock transcription factor, brain and muscle ARNT-like 1 (BMAL1). In turn, ATP7A promoted tumor cell growth through regulation of fatty acid desaturation. Copper levels negatively fed back into the circadian circuitry through sequestosome 1/p62–mediated lysosomal degradation of BMAL1. Targeting the circadian clock or fatty acid desaturation augmented cuproptosis antitumor effects. Crosstalk between the core circadian clock and copper sustains GSCs, reshaping fatty acid metabolism and promoting drug resistance, which may inform development of combination therapies for GBM.  \nIntroduction  \nGlioblastoma (GBM) represents the most prevalent and malignant primary brain tumor, with a median survival under 2 years (1) . One major challenge in GBM therapy is its marked heterogeneity, reflected in its original designation as glioblastoma multiforme. GBM cells form hierarchies topped by self-renewing, tumorigenic GBM stem cells (GSCs) that drive angiogenesis, invasion, and therapy resistance (2, 3) . Despite their recognized importance, therapies targeting GSCs have yielded inconsistent clinical benefits.  \nHeavy metals have dual roles in cellular physiology. Iron and copper act as enzyme cofactors but are toxic when levels are imbalanced. Menkes disease is an X-linked disorder caused by ATPase copper transporting alpha (ATP7A) mutations on Xq13 .3, leading to impaired copper transport. ATP7A is a transmembrane protein expressed in enterocytes, placenta, and the CNS that normally resides in the trans-Golgi network to deliver copper for cuproenzyme synthesis. When copper levels rise, ATP7A relocates to the plasma membrane to mediate efflux. Thus, metal homeostasis is  \nConflict of interest: JNR reports honoraria from Synchronicity Pharma LLC. SAK is compensated as a scientific advisor to Synchronicity Pharma LLC and received research support from the company.  \nCopyright: © 2026, Yuan et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.  \nSubmitted: February 20, 2025; Accepted: November 6, 2025;  \nPublished: January 2, 2026.  \nReference information: J Clin Invest. 20","cbCaid0IoqJ1twVQ","https://ap.wps.com/l/cbCaid0IoqJ1twVQ","pdf",11766910,17,"English","# Introduction\n## Cuproptosis and copper regulation\n## GBM resistance and stem cell hierarchy\n## Ferroptosis, copper accumulation, and cuproptosis pathways","[{\"question\":\"What is cuproptosis and how is it related to copper in cells?\",\"answer\":\"Cuproptosis is triggered by accumulation of intracellular copper, which promotes mitochondrial lipoylated protein aggregation and destabilizes iron–sulfur cluster proteins, leading to cell death.\"},{\"question\":\"How do glioblastoma stem cells respond to cuproptosis across the circadian cycle?\",\"answer\":\"GBM stem cells display relative resistance to cuproptosis with circadian variation in intracellular copper levels.\"},{\"question\":\"Which regulators connect the circadian clock to copper homeostasis and tumor growth?\",\"answer\":\"BMAL1 mediates circadian control of copper homeostasis, and ATP7A supports tumor cell growth through regulation of fatty acid desaturation; copper also feeds back to the clock via p62-mediated lysosomal degradation of BMAL1.\"}]","Glioblastoma stem cells resist cuproptosis with circadian variation of copper levels | PDF",1790596339,43]