[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-372005-105":59,"doc-detail-372005-en":130},{"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":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","eno1-mediated-deoxycytidine-synthesis-and-gemcitabine-resistance-by-stabilizing-rrm2-in-pancreatic-cancer","ENO1-mediated deoxycytidine synthesis and gemcitabine resistance by stabilizing RRM2 in pancreatic cancer","","Gemcitabine resistance shortens survival in pancreatic ductal adenocarcinoma, with upregulated deoxypyrimidine synthesis implicated but mechanisms unresolved. This study identifies ENO1 as closely linked to gemcitabine resistance and shows it increases resistance independent of glycolytic activity. ENO1 competitively binds RRM2 with STUB1, weakening RRM2 ubiquitination and degradation. ENO1-driven RRM2 aggregation elevates dNTP synthesis, thereby strengthening resistance. The ENO1–RRM2–STUB1 axis supports new therapeutic targeting strategies in pancreatic cancer.",{"@graph":69,"@context":122},[70,84,105],{"@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/eno1-mediated-deoxycytidine-synthesis-and-gemcitabine-resistance-by-stabilizing-rrm2-in-pancreatic-cancer/372005/",{"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/eno1-mediated-deoxycytidine-synthesis-and-gemcitabine-resistance-by-stabilizing-rrm2-in-pancreatic-cancer/372005.png","ImageObject",300,407,{"name":92,"@type":93},"CatatanPagi","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-25","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":39},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why is gemcitabine resistance important in pancreatic cancer?","Question",{"text":112,"@type":113},"Gemcitabine resistance leads to poor therapeutic responses in over 90% of patients, contributing to shortened survival.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does ENO1 affect gemcitabine resistance in pancreatic cancer?",{"text":117,"@type":113},"ENO1 increases pancreatic cancer resistance to gemcitabine without relying on its glycolytic enzyme activity.",{"name":119,"@type":110,"acceptedAnswer":120},"What mechanism links ENO1 to RRM2 and dNTP synthesis?",{"text":121,"@type":113},"ENO1 competitively binds RRM2 with STUB1, weakening ubiquitination and degradation of RRM2, which increases dNTP synthesis and enhances gemcitabine resistance.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},372005,1790697910,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":39,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},962090894170,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","[www.nature.com/cddis](www.nature.com/cddis)  \nARTICLE OPEN   \nENO1-mediated deoxycytidine synthesis and gemcitabine resistance by stabilizing RRM2 in pancreatic cancer  \nYongning Li1,2,3,4,5,7, Hao Wang1,2,3,4,5,7, Liwen Chen 1,2,3,4,5,7, Yanyu Gong 1,2,3,4,5,7, Dijie Zheng 1,2,3,4,5, Futang Li 1,2,3,4,5, Changhao Wu 1,2,3,4,5, Zhiwei He 1,2,3,4,5,6 and Chao Yu 1,2,3,4,5,6 ✉  \n© The Author(s) 2025  \n\n|  | Pancreatic ductal adenocarcinoma is a highly malignant solid tumor of the digestive tract, and chemoresistance to gemcitabine isan important cause of shortened survival time in patients. Upregulation of deoxypyrimidine synthesis is one of the important reasons for pancreatic cancer cells to be resistant to gemcitabine, however, the specific mechanism leading to increased deoxypyrimidine synthesis in pancreatic cancer cells is still unclear. Ribonucleotide reductase M2 subunit (RRM2) is overexpressed through unclear mechanisms in many types of human cancer significantly affects sensitivity to various chemotherapy treatments. Here, we found that high expression of enolase-1 (ENO1) is closely related to gemcitabine resistance in pancreatic cancer patients. Cellular experiments and in vivo experiments confirmed that ENO1 increases the resistance of pancreatic cancer to gemcitabine without relying on its glycolytic enzyme activity. Mechanistically, ENO1 competitively binds to RRM2 with ubiquitin E3 ligase STUB1, thereby weakening the ubiquitination and degradation of RRM2 by STUB1 . This ENO1-mediated aggregation of RRM2 protein increases the synthesis of dNTPs in pancreatic cancer cells, enhancing the resistance of pancreatic cancer to gemcitabine. Our study reveals a role of ENO1 in pancreatic cancer via RRM2-STUB1 axis and provides a scientific basis for the development of new |  |\n| --- | --- | --- |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n| therapeutic strategies targeting ENO1 . |  |  |\n|  | Cell Death and Disease (2026)17:139; [https://doi.org/10.1038/s41419-025-08061-6](https://doi.org/10.1038/s41419-025-08061-6) |  |\n|  |  |  |\n\nINTRODUCTION  \nPancreatic cancer, over 90% of which is pancreatic ductaladenocarcinoma (PDAC), is a highly aggressive gastrointestinal tumor [1] . Due to its insidious onset, lack of effective early screening markers, fewer than 20% of patients are eligible for surgical resection [2, 3] . Over the past few decades, significant advancements in cancer treatment have led to the development of targeted and immunotherapeutic drugs that have greatly improved the prognosis of various malignancies. However, these drugs do not yield satisfactory outcomes in patients with pancreatic cancer [4–6] . Currently, gemcitabine remains the firstline treatment for pancreatic cancer [7] . However, resistance to gemcitabine results in poor therapeutic responses in over 90% of patients [8–10] . Therefore, elucidating the molecular basis of gemcitabine resistance in pancreatic cancer is crucial for precisely selecting patients who will benefit from gemcitabine treatment, developing new drugs to enhance its efficacy, and improving the prognosis of pancreatic cancer.  \nGemcitabine is a deoxycytidine nucleoside analog, upon cellular uptake, is converted into a deoxynucleoside diphosphate(dCDP) analog [11], which inhibits ribonucleotide reductase, an enzyme required for the production of deoxyribonucleotide triphosphates(dCTP), thereby reducing intracellular nucleotides [12] . Once  \ngemcitabine is phosphorylated to its triphosphate form, it competes with dCTP and incorporates into nascent DNA, inducing apoptosis [13] . Multiple mechanisms contribute to its resistance, including aberrant metabolism [14, 15] and transport of gemcitabine [16, 17], and enhanced DNA repair mechanisms [18] . Recent studies have suggested that abnormal pyrimidine synthesis in pancreatic cancer cells leads to increased intracellular dCTP levels, competitively inhibiting the activity of","cbCair5RMWtnCL52","https://ap.wps.com/l/cbCair5RMWtnCL52","pdf",4452668,14,"English","# Introduction\n## Pancreatic cancer burden and gemcitabine resistance\n## Gemcitabine mechanism and resistance pathways\n## RRM2 and abnormal pyrimidine synthesis\n## ENO1 functions and rationale for investigation","[{\"question\":\"Why is gemcitabine resistance important in pancreatic cancer?\",\"answer\":\"Gemcitabine resistance leads to poor therapeutic responses in over 90% of patients, contributing to shortened survival.\"},{\"question\":\"How does ENO1 affect gemcitabine resistance in pancreatic cancer?\",\"answer\":\"ENO1 increases pancreatic cancer resistance to gemcitabine without relying on its glycolytic enzyme activity.\"},{\"question\":\"What mechanism links ENO1 to RRM2 and dNTP synthesis?\",\"answer\":\"ENO1 competitively binds RRM2 with STUB1, weakening ubiquitination and degradation of RRM2, which increases dNTP synthesis and enhances gemcitabine resistance.\"}]","ENO1-mediated deoxycytidine synthesis and gemcitabine resistance by stabilizing RRM2 in pancreatic cancer | PDF",1790193439,35]