RIP3介导的坏死性凋亡是心肌梗死(MI)后心肌细胞死亡的重要形式。高迁移率蛋白家族(HMG)是DNA结合蛋白，调控DNA的转录，但HMGXB4的作用尚无报道。我们前期研究发现HMGXB4在MI后心肌中表达早期显著降低，并与RIP3表达呈相反趋势；体外培养的心肌细胞HMGXB4敲低促进坏死性凋亡，而过表达起保护作用；心肌细胞条件性HMGXB4敲除MI小鼠心肌坏死性凋亡加重，心肌局部过表达HMGXB4可改善坏死性凋亡和心功能。结合生物信息学分析，我们推测：HMGXB4在核内与RIP3启动子结合抑制转录，胞外竞争性结合TLR4抑制TLR4-RIP1/3-MLKL信号通路减少坏死性凋亡。本项目拟采用启动子定点突变、CHIP、EMSA和Co-IP技术，明确HMGXB4调控RIP3的作用机制；研究结果将首次阐明HMGXB4在MI后心肌细胞坏死性凋亡中的作用和机制，为临床转化研究奠定基础和科学依据。

RIP3-mediated necroptosis is the main mechanism of cardiomyocyte death after myocardial infarction (MI). The High Mobility Group-box family (HMG) is DNA binding proteins regulating DNA transcription, however, the role of HMGXB4 has not been reported. Our preliminary investigation showed that HMGXB4 expression was significantly down-regulated in myocardium at early-stage post MI with the opposite trend of RIP3 expression. Moreover, silence of HMGXB4 in cardiomyocytes in vitro increased necroptosis, while HMGXB4 overexpression significantly reduced necroptosis. Consistently, we found cardiomyocyte-conditional HMGXB4 deletion in mice aggravated necroptosis, while cardiac overexpression of HMGXB4 alleviated necroptosis and cardiac dysfunction after MI in vivo. Combining with bioinformatics analysis, we postulate that HMGXB4 binds to RIP3 promoter in the nucleus which inhibits necroptosis by repressing RIP3 gene transcription, and blocks TLR4-RIP1/3-MLKL pathway extracellularly. In our study, we will employ promoter site-directed mutagenesis, CHIP, EMSA and Co-IP to elucidate the mechanism of HMGXB4 regulating RIP3. The findings will firstly reveal the role and mechanism of HMGXB4 in necroptosis after MI, providing theoretical basis of the clinical translational medicine.