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Using quantitative proteomics, RNA-seq, and single-nucleus RNA-seq, HMGB2 expression is shown to rise in high-regenerative cardiomyocyte populations after injury and decline during postnatal development. Cardiomyocyte-specific loss reduces proliferation and impairs regeneration after apical resection in neonatal mice, whereas overexpression enhances proliferation and repair after myocardial infarction in adult mice. Mechanistically, HMGB2 activates HIF-1α–mediated glycolysis by binding MTA2 and blocking its ubiquitination degradation, stabilizing HIF-1α; restoring HIF-1α or MTA2 further promotes repair, suggesting HMGB2-MTA2-HIF-1α 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":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/hmgb2-promotes-cardiomyocyte-proliferation-and-heart-regeneration-through-mta2-driven-metabolic-reprogramming/439554/",{"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/hmgb2-promotes-cardiomyocyte-proliferation-and-heart-regeneration-through-mta2-driven-metabolic-reprogramming/439554.png","ImageObject",300,407,{"name":92,"@type":93},"Bintang","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-02","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":81},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What role does HMGB2 play in heart regeneration and cardiomyocyte proliferation?","Question",{"text":112,"@type":113},"HMGB2 acts as a key regulator that promotes cardiomyocyte proliferation and supports heart regeneration after injury. Its expression increases in highly regenerative cardiomyocyte populations post-injury and decreases during postnatal development.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How do HMGB2 loss and overexpression affect regeneration in mice?",{"text":117,"@type":113},"Cardiomyocyte-specific HMGB2 knockdown reduces cardiomyocyte proliferation and impairs heart regeneration after apical resection in neonatal mice. HMGB2 overexpression enhances cardiomyocyte proliferation and facilitates cardiac regeneration and repair after myocardial infarction in adult mice.",{"name":119,"@type":110,"acceptedAnswer":120},"What mechanism links HMGB2 to increased glycolysis and HIF-1α stability?",{"text":121,"@type":113},"HMGB2 promotes cardiomyocyte proliferation by activating HIF-1α–mediated glycolysis. It directly interacts with MTA2 and inhibits MTA2 ubiquitination degradation, stabilizing HIF-1α, as supported by IP-MS analysis.","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},439554,1790740990,{"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":81,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":56,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":144},962085564381,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","RESEARCH ARTICLE  \n[www.advancedscience.com](www.advancedscience.com)  \nHMGB2 Promotes Cardiomyocyte Proliferation and Heart Regeneration Through MTA2-Driven Metabolic Reprogramming  \nLiu-Hua Zhou, Ling-Feng Gu, Yi-Xi Chen, Peng Jing, Tong-Tong Yang, Ye He, Yu-Lin Bao, Xiang-Zheng Zhang, Chong Du, Si-Bo Wang, Tian-Kai Shan, Jia-Yi Chen, Hao Wang, Qi-Ming Wang, Li-Ping Xie, Yang Zhao, Yong Ji, and Lian-Sheng Wang*  \nThe neonatal heart possesses the unique ability to regenerate post-injury. Underlying related mechanisms and reactivation of this process are crucial for regeneration medicine. Using quantitative proteomics with tandem mass tag labeling, RNA-sequencing (RNA-seq) and single-nucleus RNA-seq dataset analyses, high mobility group box 2 (HMGB2) is identified as a key regulator of cardiomyocyte proliferation, whose expression declines during postnatal heart development and increases in the high regenerative potential cardiomyocyte populations in hearts post-injury. Cardiomyocyte-specific HMGB2 knockdown curtails cardiomyocyte proliferation and impairs heart regeneration following apical resection in neonatal mice, while cardiomyocyte-specific HMGB2 overexpression enhances cardiomyocyte proliferation and facilitates cardiac regeneration and repair in adult mice post-myocardial infarction. Mechanistically, RNA-seq analysis reveals that HMGB2 promotes cardiomyocyte proliferation via activating hypoxia inducible factor 1ɑ (HIF-1􀀂)-mediated glycolysis. This study further finds HMGB2 can directly interact with metastasis-associated protein 2 (MTA2) and inhibit its ubiquitination degradation to stabilize HIF-1􀀂 protein through immunoprecipitation-mass spectrometry (IP-MS) analysis. Finally, overexpression of HIF-1􀀂 or MTA2 also promotes cardiomyocyte proliferation and cardiac repair in adult mice following MI. Taken together, these findings highlight that HMGB2 plays a crucial role in promoting heart regeneration through regulating glycolysis. Activating the HMGB2-MTA2-HIF-1􀀂 axis might serve as a potential therapeutic option for regenerative therapies post-myocardial injury.  \n1. Introduction  \nIschemic heart disease is a leading cause of cardiovascular morbidity and mortality worldwide. [1,2] Current treatments for myocardial infarction (MI) primarily focus on restoring blood flow to the infarcted coronary artery and improving myocardial perfusion, rather than fundamentally resolving the replenishment of dying cardiomyocytesor the repair of necrotic myocardium. [3–6] Therefore, addressing these aspects might further improve the long-term outcomes of patients with acute myocardial infarction. It is established that newborn mice can achieve complete functional and morphological heart repair through endogenous regeneration following apical resection (AR) . However, this capacity rapidly diminishes within seven days after birth. [7–9] Elucidating the mechanisms of neonatal heart regeneration and identifying effective molecular targets to reactivate the cell cycle of mature cardiomyocytes may provide valuable strategies and insights for treating myocardial injury.  \nAs a member of the high mobility group box (HMGB) protein family, high mobility group box 2 (HMGB2) is one of the earliest identified and most ubiquitously  \nL.-H. Zhou, L.-F. Gu, Y.-X. Chen, P. Jing, T.-T. Yang, Y. He, Y.-L. Bao, C. Du, S.-B. Wang, T.-K. Shan, J.-Y. Chen, H. Wang, Q.-M. Wang, L.-S. Wang Department of Cardiology  \nthe First Affiliated Hospital with Nanjing Medical University Nanjing 210029, China  \nE-mail: [drlswang@njmu.edu.cn](drlswang@njmu.edu.cn)  \nThe ORCID identification number(s) for the author(s) of this article  \ncan be found under [https://doi.org/10.1002/advs.202505820](https://doi.org/10.1002/advs.202505820)[ ](https://doi.org/10.1002/advs.202505820)© 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 reproducti","cbCaituvzgMXHbzw","https://ap.wps.com/l/cbCaituvzgMXHbzw","pdf",5619734,"English","# Introduction\n## Neonatal cardiac regenerative capacity and its decline after birth\n## HMGB2 background and rationale for studying cardiomyocyte proliferation and regeneration\n## Study aims and mechanistic hypothesis","[{\"question\":\"What role does HMGB2 play in heart regeneration and cardiomyocyte proliferation?\",\"answer\":\"HMGB2 acts as a key regulator that promotes cardiomyocyte proliferation and supports heart regeneration after injury. Its expression increases in highly regenerative cardiomyocyte populations post-injury and decreases during postnatal development.\"},{\"question\":\"How do HMGB2 loss and overexpression affect regeneration in mice?\",\"answer\":\"Cardiomyocyte-specific HMGB2 knockdown reduces cardiomyocyte proliferation and impairs heart regeneration after apical resection in neonatal mice. HMGB2 overexpression enhances cardiomyocyte proliferation and facilitates cardiac regeneration and repair after myocardial infarction in adult mice.\"},{\"question\":\"What mechanism links HMGB2 to increased glycolysis and HIF-1α stability?\",\"answer\":\"HMGB2 promotes cardiomyocyte proliferation by activating HIF-1α–mediated glycolysis. It directly interacts with MTA2 and inhibits MTA2 ubiquitination degradation, stabilizing HIF-1α, as supported by IP-MS analysis.\"}]","HMGB2 Promotes Cardiomyocyte Proliferation and Heart Regeneration Through MTA2-Driven Metabolic Reprogramming | PDF",1790689188,48]