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

作者：Liuhua Zhou, Lingfeng Gu, Yi‐Xi Chen, Peng Jing, Tongtong Yang, Ye He, Yu‐Lin Bao, Xiangzheng Zhang, Chong Du, Sibo Wang, Tiankai Shan, Jiayi Chen, Hao Wang, Qiming Wang, Liping Xie, Yang Zhao, Yong Ji, Liansheng Wang · 发表于：Advanced Science · 年份：2025 · DOI：10.1002/advs.202505820 · 被引用次数：4 · 研究领域：Congenital heart defects research、Tissue Engineering and Regenerative Medicine、Cardiac Fibrosis and Remodeling

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 pro...