HMGB2 Promotes Cardiomyocyte Proliferation and Heart Regeneration Through MTA2‐Driven Metabolic Reprogramming

The 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-1α)-mediated glycolysis. This study further finds HMGB2 can directly interact with metastasis-associated protein 2 (MTA2) and inhibit its ubiquitination degradation to stabilize HIF-1α protein through immunoprecipitation-mass spectrometry (IP-MS) analysis. Finally, overexpression of HIF-1α 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-1α axis might serve as a potential therapeutic option for regenerative therapies post-myocardial injury.