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Transcriptomic and clinical colorectal cancer data from TCGA were analyzed to assess cuproptosis-related effects using WGCNA to identify differentially expressed cuproptosis-associated genes. A prognostic model based on six key genes was built with LASSO and random forest, then validated on two independent external datasets. The model stratified patients into high- and low-risk groups with differences in disease stage, immune features, tumor mutational burden, and treatment response. P4HA1 emerged as a key gene, and its downregulation suppressed tumor progression and reduced colorectal cancer cell sensitivity to the cuproptosis inducer elesclomol via oxidative stress-related mechanisms, supporting P4HA1 as a therapeutic target.",{"@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":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/development-of-a-prognostic-gene-signature-and-exploration-of-p4ha1-in-the-modulation-of-cuproptosis-in-colorectal-cancer/332927/",{"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/development-of-a-prognostic-gene-signature-and-exploration-of-p4ha1-in-the-modulation-of-cuproptosis-in-colorectal-cancer/332927.png","ImageObject",300,407,{"name":92,"@type":93},"Theodora","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-15","2026-09-21",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},"What was the purpose of analyzing colorectal cancer data in this study?","Question",{"text":112,"@type":113},"To determine how cuproptosis is involved in colorectal cancer and to build a prognostic framework reflecting cuproptosis-related biology.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How was the prognostic gene signature constructed and validated?",{"text":117,"@type":113},"Differential cuproptosis-related genes were identified using WGCNA, then key genes were selected with LASSO and random forest to form a six-gene prognostic model, which was validated using two independent external datasets.",{"name":119,"@type":110,"acceptedAnswer":120},"What role does P4HA1 play according to the study results?",{"text":121,"@type":113},"P4HA1 was identified as a key gene of interest; downregulation inhibited tumor progression and increased resistance-related effects toward the cuproptosis inducer elesclomol, potentially through oxidative stress mechanisms.","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},332927,1790012773,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"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,"preview_page_count":4},687197207919,"https://ap-avatar.wpscdn.com/avatar/a000253d6f5f7c60be?x-image-process=image/resize,m_fixed,w_180,h_180&k=1779446848396160552","[www. nature.com/scientificreports](www. nature.com/scientificreports)  \nOPEN  \nDevelopment of a prognostic gene signature and exploration of P4HA1 in the modulation of cuproptosis in colorectal cancer  \nRenJie Jiang1,2, LinLin Ruan3, Taohui Ding1, Hongtao Wan1, Yanglin Chen1, XiaoJian Zhu1, Zhijiang Huang1, DengkeYao1, Ming Li4, BoYi1􀀍 & Dan Liu2􀀍  \nCuproptosis, a newly identified form of cell death, has drawn increasing attention for its association with various cancers, though its specific role in colorectal cancer (CRC) remains unclear. In this study, transcriptomic and clinical data from CRC patients available in theTCGA database were analyzed to investigate the impact of cuproptosis. Differentially expressed genes linked to cuproptosis were identified using Weighted Gene Co-Expression Network Analysis (WGCNA). Key genes were further refined through LASSO regression and random forest approaches, culminating in the development of a prognostic model comprising six critical genes. The predictive accuracy of the model was validated using two independent external datasets. This model effectively stratified patients into high-and low-risk groups, which exhibited significant differences in disease stage, immune landscape, tumor mutational burden, and therapeutic response, underscoring the robustness of the model. P4HA1 was identified as a key gene of interest, where downregulation was found to inhibit tumor progression in single-cell sequencing analyses and in vitro experiments. Additionally, suppression of P4HA1 enhanced the sensitivity ofCRC cells to the cuproptosis inducer elesclomol (ES), potentially through oxidative stress mechanisms. In conclusion, this study proposes a prognostic model based on six cuproptosisrelated genes that could aid in personalizing CRC treatment. Furthermore, P4HA1 emerges as a promising therapeutic target.  \nKeywords Cuproptosis, Copper, Colorectal cancer, Prognostic signature, P4HA1, Oxidative stress  \nAbbreviations  \nCu  \nCRC  \nES WGCNA LASSO KEGG  \nGO  \nTCGA  \nGEO  \nCRGs  \nROS  \nTCA  \nTPM  \nUMAP  \nCopper Colorectal cancer Elesclomol  \nWeighted gene co-expression network analysis Least absolute shrinkage and selection operator Kyoto encyclopedia of genes and genomes  \nGene ontology The cancer genome atlas Gene expression omnibus Cuproptosis-related genes Reactive oxygen species Tricarboxylic acid Transcripts per million  \nUniform manifold approximation and projection  \n12nd Abdominal Surgery Department, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Nanchang 330029, Jiangxi, People’s Republic of China. 2School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang 330006, People’s Republic of China. 3Department of Pharmacy, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Nanchang 330029, Jiangxi, People’s Republic of China. 4Jiangxi Key Laboratory of Translational Cancer Research, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Nanchang 330029, Jiangxi, People’s Republic of China. 􀀍 email:  \n[yibo@ncmc.edu.cn](yibo@ncmc.edu.cn); [liudan1201jx@ncu.edu.cn](liudan1201jx@ncu.edu.cn)  \n[www. nature.com/scientificreports/](www. nature.com/scientificreports/)  \nFC  \nDEGs  \nGSVA  \nTOM  \nRF  \nOS  \nROC  \nAUC  \nSDANOVA BP  \nCC  \nMF  \nTTM  \nHRssGSEAPCATregs ESTIMATEscRNA-seq  \nFold change  \nDifferentially expressed genes Gene set variation analysis Topological overlap matrix Random forest  \nOverall survival  \nReceiver operator characteristic Area under the curve  \nStandard deviation Analysis of variance Biological process Cellular component Molecular function Tetrathiomolybdate Hazard ratio  \nSingle-sample gene set enrichment analysis Principal component analysis Regulatory T cell  \nEstimation of stromal and immune cells in malignant tumor tissues using expression data Single-cell RNA sequencing  \nColorectal cancer (CRC) ranks as the third most common and second most fatal cancer worl","cbCaidcwf4IENsv3","https://ap.wps.com/l/cbCaidcwf4IENsv3","pdf",23121077,23,"English","# Introduction\n## Clinical background of colorectal cancer and need for prognostic markers\n## Biological basis of copper and cuproptosis\n## Mechanistic overview of cuproptosis in mitochondria","[{\"question\":\"What was the purpose of analyzing colorectal cancer data in this study?\",\"answer\":\"To determine how cuproptosis is involved in colorectal cancer and to build a prognostic framework reflecting cuproptosis-related biology.\"},{\"question\":\"How was the prognostic gene signature constructed and validated?\",\"answer\":\"Differential cuproptosis-related genes were identified using WGCNA, then key genes were selected with LASSO and random forest to form a six-gene prognostic model, which was validated using two independent external datasets.\"},{\"question\":\"What role does P4HA1 play according to the study results?\",\"answer\":\"P4HA1 was identified as a key gene of interest; downregulation inhibited tumor progression and increased resistance-related effects toward the cuproptosis inducer elesclomol, potentially through oxidative stress mechanisms.\"}]","Development of a prognostic gene signature and exploration of P4HA1 in the modulation of cuproptosis in colorectal cancer | PDF",1790000039,58]