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In young hearts, CBX7 supports cardiomyocyte proliferation, whereas in aged hearts CBX7 forms liquid–liquid phase separation with ATP7A, trapping ATP7A intracellularly and reducing membrane trafficking and copper efflux to trigger cuproptosis. High-throughput screening identifies α-Amyrenone as a selective CBX7 inhibitor that disrupts CBX7–ATP7A LLPS, restores ATP7A trafficking and copper efflux, and improves function while reducing fibrosis and arrhythmias, including via engineered conductive antioxidant and pro-angiogenic hydrogel delivery.",{"@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/engineered-multifunctional-hydrogel-delivering-novel-cbx7-inhibitor-modulates-cuproptosis-via-liquid-liquid-phase-separation-to-restore-cardiac-function-in-aged-myocardial-infarction/439666/",{"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/engineered-multifunctional-hydrogel-delivering-novel-cbx7-inhibitor-modulates-cuproptosis-via-liquid-liquid-phase-separation-to-restore-cardiac-function-in-aged-myocardial-infarction/439666.png","ImageObject",300,407,{"name":92,"@type":93},"Rizky","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",13,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"How does CBX7 influence cardiac outcomes differently in young versus aged hearts?","Question",{"text":113,"@type":114},"CBX7 promotes cardiomyocyte proliferation in young hearts, but in aged hearts it forms liquid–liquid phase separation with ATP7A, trapping ATP7A and reducing copper efflux, which triggers cuproptosis.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"What is the role of the CBX7–ATP7A liquid–liquid phase separation in cuproptosis?",{"text":118,"@type":114},"The CBX7–ATP7A LLPS traps ATP7A intracellularly, lowers membrane trafficking and copper efflux, and activates cuproptosis, contributing to injury after myocardial ischemia–reperfusion.",{"name":120,"@type":111,"acceptedAnswer":121},"How does the engineered conductive hydrogel improve therapeutic effects in aged myocardial infarction models?",{"text":122,"@type":114},"The hydrogel enables single-injection, controlled release of the CBX7 inhibitor, alleviates cuproptosis-related mitochondrial injury, and supports ATP7A trafficking and copper efflux to suppress cuproptosis, improving structural, functional, and electrophysiological outcomes.","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},439666,1790764399,{"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},962085564807,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","RESEARCH ARTICLE  \n[www.advancedscience.com](www.advancedscience.com)  \nEngineered Multifunctional Hydrogel Delivering Novel CBX7 Inhibitor Modulates Cuproptosis Via Liquid–Liquid Phase Separation to Restore Cardiac Function in Aged Myocardial Infarction  \nJun Liu, Peng Qu, Jiao Shi, Tingting Liang, Yao Gu, Xue Li, Cui Ma, Danyang Zhao, Feila Liu, Qi Liang,* Panke Cheng,* and Qian Lei*  \nCardiac repair after myocardial ischemia–reperfusion (MIR) declines with aging. This study shows that Chromobox 7 (CBX7) acts in an age-dependent manner, in young hearts, it promotes cardiomyocyte proliferation, whereas in aged hearts, CBX7 forms liquid–liquid phase separation (LLPS) with ATP7A, trapping ATP7A intracellularly, reducing membrane trafficking and copper efflux, and triggering cuproptosis. High-throughput screening identifies 􀀂-Amyrenone (􀀂Ae) as a selective CBX7 inhibitor that disrupts CBX7-ATP7ALLPS, restores ATP7A trafficking and copper efflux, and improves cardiac function while reducing fibrosis and arrhythmias. Single-cell RNA-seq shows MIR-induced cuproptosis-related loss is concentrated in NR4A3 positive cardiomyocytes and RGCC positive capillary endothelial cells in aged hearts. To enhance delivery, this study engineered a multifunctional conductive hydrogel with antioxidant, pro-angiogenic, immunomodulatory, O2 releasing and electrical properties. Loaded with 􀀂Ae, this single-injection hydrogel provides controlled release, alleviates cuproptosis-related mitochondrial injury, and pairs its intrinsic repair capacity with CBX7 inhibition to drive ATP7Atrafficking, enhance copper efflux, and suppress cuproptosis. In aged mouse and Bama minipig MIR models, this strategy improves structural, functional, and electrophysiological outcomes, supporting translational potential.  \n1. Introduction  \nThe rate of adult cardiomyocyte turnover in mammals significantly declines with age,[1] and the reduction in regenerative capacity is primarily attributed to cell cycle exit following differentiation, changes in metabolic pathways, and alterations in chromatin structure. [2] Previous studies have shown that modulating key molecular targets and their associated signaling pathways can promote cardiomyocyte regeneration in mature hearts. [3] For example, inhibition of Hippo or activation of YAP in the Hippo-YAP pathway allows cardiomyocytesto re-enter the cell cycle and proliferate;[4] activation of the Wnt/􀀂-catenin signaling also promotes proliferation;[5] while activating the ERBB2-Neuregulin pathway not only promotes cardiomyocyte regeneration but also induces epithelial-mesenchymal transition-like responses, which facilitate cardiac repair.[6] On the other hand, studies  \nJ. Liu, P. Qu, J. Shi, Y. Gu, X. Li, Q. Liang Department of Clinical Laboratory  \nAffiliated Hospital of North Sichuan Medical College Nanchong 637000, China  \nE-mail: [lixh1005@nsmc.edu.cn](lixh1005@nsmc.edu.cn)  \nJ. Liu, P. Qu, J. Shi, Y. Gu, X. Li, Q. Liang School of Laboratory Medicine North Sichuan Medical College Nanchong 637007, China  \nJ. Liu, P. Qu, J. Shi, Y. Gu, X. Li, Q. Liang Translational Medicine Research Center North Sichuan Medical College Nanchong 637007, China  \nThe ORCID identification number(s) for the author(s) of this article  \ncan be found under [https://doi.org/10.1002/advs.202511630](https://doi.org/10.1002/advs.202511630)[ ](https://doi.org/10.1002/advs.202511630)© 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.  \nDOI: 10.1002/advs.202511630  \nT. Liang, P. Cheng  \nInstitute of Cardiovascular Diseases & Department of Cardiology Sichuan Provincial People’s Hospital  \nSchool of Medicine  \nUniversity of Electronic Science and Technology of China Chengdu 610072, China  \nE-mail: [chengpk1002@uestc.edu.cn](chengpk1002@uestc.edu.cn)  \nC. Ma  \nDepartment","cbCaigLH7mAtt4GI","https://ap.wps.com/l/cbCaigLH7mAtt4GI","pdf",5912324,17,"English","# Introduction\n## Age-related decline in cardiomyocyte regeneration\n## CBX7 function and cuproptosis mechanism in aged hearts\n## Targeting CBX7–ATP7A liquid–liquid phase separation\n## High-throughput identification of a selective CBX7 inhibitor\n## Engineered multifunctional conductive hydrogel delivery strategy","[{\"question\":\"How does CBX7 influence cardiac outcomes differently in young versus aged hearts?\",\"answer\":\"CBX7 promotes cardiomyocyte proliferation in young hearts, but in aged hearts it forms liquid–liquid phase separation with ATP7A, trapping ATP7A and reducing copper efflux, which triggers cuproptosis.\"},{\"question\":\"What is the role of the CBX7–ATP7A liquid–liquid phase separation in cuproptosis?\",\"answer\":\"The CBX7–ATP7A LLPS traps ATP7A intracellularly, lowers membrane trafficking and copper efflux, and activates cuproptosis, contributing to injury after myocardial ischemia–reperfusion.\"},{\"question\":\"How does the engineered conductive hydrogel improve therapeutic effects in aged myocardial infarction models?\",\"answer\":\"The hydrogel enables single-injection, controlled release of the CBX7 inhibitor, alleviates cuproptosis-related mitochondrial injury, and supports ATP7A trafficking and copper efflux to suppress cuproptosis, improving structural, functional, and electrophysiological outcomes.\"}]","Engineered Multifunctional Hydrogel Delivering Novel CBX7 Inhibitor Modulates Cuproptosis Via Liquid - Liquid Phase Separation to Restore Cardiac Function in Aged Myocardial Infarction | PDF",1790689769,43]