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CNNM4 expression is evaluated across in vitro, in vivo, and patient samples, with functional effects tested via CNNM4 silencing, ferroptosis-linked mechanistic analysis, and therapeutic reversal using relevant modulators.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/role-of-cnnm4-in-the-progression-of-cholangiocarcinoma-implications-for-ferroptosis-and-therapeutic-potential/356376/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/role-of-cnnm4-in-the-progression-of-cholangiocarcinoma-implications-for-ferroptosis-and-therapeutic-potential/356376.png","ImageObject",300,407,{"name":42,"@type":43},"Liam","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-31","2026-09-23",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",10,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"What is the main purpose of the study on CNNM4 and cholangiocarcinoma?","Question",{"text":63,"@type":64},"To unravel how CNNM4 contributes to the initiation and progression of cholangiocarcinoma, and to connect its effects to ferroptosis and therapeutic potential.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How was CNNM4 investigated in the study?",{"text":68,"@type":64},"CNNM4 protein and gene expression were assessed in vitro, in vivo, and in patients with CCA, followed by functional testing using CNNM4 silencing approaches and mechanistic proteomic analysis.",{"name":70,"@type":61,"acceptedAnswer":71},"What key findings link CNNM4 to ferroptosis in CCA?",{"text":72,"@type":64},"CNNM4 was upregulated in human and experimental models, and CNNM4 deficiency reduced multiple malignant phenotypes. Proteomic analysis identified nuclear protein 1 as an upstream regulator of CNNM4-induced ferroptosis, leading to cell death, and deferiprone could reverse reduced proliferation.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},356376,1790245974,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,115,120,123,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":97,"doc_module":4,"doc_module_name":25,"category_name":98,"show_sort_weight":99,"slug":100},5,"Comic",60,"comic",{"id":102,"doc_module":4,"doc_module_name":25,"category_name":103,"show_sort_weight":104,"slug":105},6,"Technology",50,"technology",{"id":107,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":108,"slug":109},7,40,"healthcare",{"id":111,"doc_module":4,"doc_module_name":25,"category_name":112,"show_sort_weight":113,"slug":114},8,"Research & Report",30,"research-report",{"id":116,"doc_module":4,"doc_module_name":25,"category_name":117,"show_sort_weight":118,"slug":119},9,"Religion & Spirituality",20,"religion-spirituality",{"id":118,"doc_module":4,"doc_module_name":25,"category_name":121,"show_sort_weight":118,"slug":122},"World Cup","world-cup",{"id":55,"doc_module":4,"doc_module_name":25,"category_name":124,"show_sort_weight":55,"slug":125},"Lifestyle","lifestyle",{"id":127,"doc_module":4,"doc_module_name":25,"category_name":128,"show_sort_weight":97,"slug":129},19,"General","general",{"code":4,"msg":82,"data":131},{"doc_id":79,"user_id":132,"nickname":42,"user_avatar":133,"doc_module":4,"category_id":107,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":139,"language":140,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":12,"update_tm":144,"read_time":113},8796095461564,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","GI cancer  \n► Additional supplemental material is published online only. To view, please visit the journal online ([https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.1136/gutjnl-2024-333255](10.1136/gutjnl-2024-333255)) .  \nFor numbered affiliations see end of article.  \nCorrespondence to  \nMaria Luz Martinez-Chantar; [mlmartinez@cicbiogune.es](mlmartinez@cicbiogune.es)  \nMM-G and NG-U contributed equally.  \nReceived 9 July 2024 Accepted 6 February 2025  \n► [https://doi.org/10.1136/](https://doi.org/10.1136/)[ ](https://doi.org/10.1136/)[gutjnl-2024-335061](gutjnl-2024-335061)  \n© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.  \nTo cite: Mercado-Gómez M, Goikoetxea-Usandizaga N, Giné AE, et al. Gut Epub ahead of print: [please include Day Month Year] . doi:10.1136/ gutjnl-2024-333255  \nOriginal research  \nRole of CNNM4 in the progression of cholangiocarcinoma: implications for ferroptosis and therapeutic potential  \nMaria Mercado-Gómez  , 1 Naroa Goikoetxea-Usandizaga,1,2 Alvaro Eguileor Giné, 1 Miguel A Merlos Rodrigo,3 Marta Bento Afonso,4 Mikel Azkargorta,5  \nLeidy Estefanía Zapata-Pavas,1 Claudia M Rejano-Gordillo,1 Marta R Romero,2,6 Isabel Mendizabal,7,8 Pedro M Rodrigues,2,8,9 Hanghang Wu, 10  \nRubén Rodríguez-Agudo,1 Marina Serrano-Maciá,1 Paula Olaizola,9 Jon Ander Barrenechea-Barrenechea,1 Irene González Recio, 1  \nMaite G Fernandez-Barrena  ,2,11 Diletta Overi  , 12 Eugenio Gaudio, 12 Ute Schaeper, 13 Saioa Garcia-Longarte  ,7 Mariana Yáñez-Bartolomé,14,15 Patricia Peña-SanFelix,1 Clàudia Gil-Pitarch,1 Ainhoa Lapitz,9 Hana Michalkova,3 Zbynek Heger,3 Carolina Conter, 1 Rocio I R Macias  ,2,6 Arkaitz Carracedo,7,8 Jesús Bañales,2,8,9,16 Victor Moreno  , 17 Angela Lamarca, 18 Rajat Singh, 19,20 Teresa Cardoso Delgado, 1 Luis Alfonso Martínez-Cruz,1 Felix Elortza,21 Matias A Avila  ,2,11 César Martín,22 Tian V. Tian  , 14,15 Teresa Macarulla, 14,15 Daniela Buccella,23 Francisco Javier Cubero  ,2,10 Diego F Calvisi,24,25 Guido Carpino  , 12 Jose J G Marin  ,2,6 Cecília M P Rodrigues,4  \nMaria Luz Martinez-Chantar  1,2  \nABSTRACT  \nBackground and objective Cholangiocarcinoma (CCA) is a heterogeneous neoplasm of the biliary epithelium that easily infiltrates, metastasises and recurs. Magnesium disbalance is a hallmark of CCA, with the magnesium transporter cyclin M4 (CNNM4) being a key driver of various hepatic diseases. This study aims to unravel the role of CNNM4 in the initiation and progression of CCA.  \nDesign CNNM4 protein and gene expression were assessed in vitro, in vivo and in patients with CCA.  \nSilencing of CNNM4 was effectively achieved by using small interfering RNA (siRNA) or short hairpin RNA in CCA cell lines and GalNAc-conjugated siRNA in a transposonbased CCA mice model. The impact of CNNM4 on tumour cell proliferation, migration and invasion to the lungs was evaluated using the chicken chorioallantoic membrane model. Proteomic analysis was employed to elucidate the underlying molecular mechanisms.  \nResults CNNM4 was upregulated in CCA samples from humans, mice and cell lines. Functional studies demonstrated that CNNM4 deficiency attenuates cell growth, chemoresistance, migration, invasion, cancer stem cell properties and Warburg effect in vitro and in vivo. Proteomic analysis identified nuclear protein 1 asan upstream regulator of CNNM4-induced ferroptosis in CCA, ultimately leading to cell death. The iron chelator deferiprone could reverse the decreased proliferation induced by CNNM4 silencing, while inhibition of the heme oxygenase-1 by zinc protoporphyrin IX affected only  \nWHAT IS ALREADY KNOWN ON THIS TOPIC  \n\n| ⇒ Maintaining magnesium ion (Mg2+) homeostasis is crucial for various physiological processes. The Mg2+ transporter cyclin M4 (CNNM4) has emerged as a key player in liver diseases such as metabolic dysfunctionassociated steatotic liver disease (NASH) and drug induced liver injury ","cbCaicRgPWXpBxKY","https://ap.wps.com/l/cbCaicRgPWXpBxKY","pdf",12800223,12,"English","# Abstract\n## Background and objective\n## Design\n## Results\n## Conclusion\n# Introduction\n## Cholangiocarcinoma classification and prognosis\n## Treatment challenges and need for new therapies\n# What is already known on this topic\n# What this study adds\n# How this study might affect research, practice or policy","[{\"question\":\"What is the main purpose of the study on CNNM4 and cholangiocarcinoma?\",\"answer\":\"To unravel how CNNM4 contributes to the initiation and progression of cholangiocarcinoma, and to connect its effects to ferroptosis and therapeutic potential.\"},{\"question\":\"How was CNNM4 investigated in the study?\",\"answer\":\"CNNM4 protein and gene expression were assessed in vitro, in vivo, and in patients with CCA, followed by functional testing using CNNM4 silencing approaches and mechanistic proteomic analysis.\"},{\"question\":\"What key findings link CNNM4 to ferroptosis in CCA?\",\"answer\":\"CNNM4 was upregulated in human and experimental models, and CNNM4 deficiency reduced multiple malignant phenotypes. Proteomic analysis identified nuclear protein 1 as an upstream regulator of CNNM4-induced ferroptosis, leading to cell death, and deferiprone could reverse reduced proliferation.\"}]","Role of CNNM4 in the progression of cholangiocarcinoma: implications for ferroptosis and therapeutic potential | PDF",1790125086]