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

Abstract 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.