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Underlying related mechanisms and reactivation of this process are crucial for regeneration medicine. Using quantitative proteomics with tandem mass tag labeling, RNA\u2010sequencing (RNA\u2010seq) and single\u2010nucleus RNA\u2010seq 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\u2010injury. Cardiomyocyte\u2010specific HMGB2 knockdown curtails cardiomyocyte proliferation and impairs heart regeneration following apical resection in neonatal mice, while cardiomyocyte\u2010specific HMGB2 overexpression enhances cardiomyocyte proliferation and facilitates cardiac regeneration and repair in adult mice post\u2010myocardial infarction. Mechanistically, RNA\u2010seq analysis reveals that HMGB2 promotes cardiomyocyte proliferation via activating hypoxia inducible factor 1\u0251 (HIF\u20101\u03b1)\u2010mediated glycolysis. This study further finds HMGB2 can directly interact with metastasis\u2010associated protein 2 (MTA2) and inhibit its ubiquitination degradation to stabilize HIF\u20101\u03b1 protein through immunoprecipitation\u2010mass spectrometry (IP\u2010MS) analysis. Finally, overexpression of HIF\u20101\u03b1 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\u2010MTA2\u2010HIF\u20101\u03b1 axis might serve as a potential therapeutic option for regenerative therapies post\u2010myocardial injury.<\/jats:p>","DOI":"10.1002\/advs.202505820","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T20:35:59Z","timestamp":1760560559000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["HMGB2 Promotes Cardiomyocyte Proliferation and Heart Regeneration Through MTA2\u2010Driven Metabolic Reprogramming"],"prefix":"10.1002","volume":"13","author":[{"given":"Liu\u2010Hua","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Cardiology the First Affiliated Hospital with Nanjing Medical University  Nanjing 210029 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling\u2010Feng","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Cardiology the First Affiliated Hospital 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