Duan Jinfeng, Cao Zijun, Zhou Zijun, Huang Xinyi, Zhao Jikai, Huang Yuting, Huang Tao, Meng Shan, Chen Xin, Hong Tao, Su Tong, Xing Bo, Yu Liming, Wang Huishan
State Key Laboratory of Frigid Zone Cardiovascular Disease, Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning 110016, PR China; Postgraduate College, China Medical University, 77 Puhe Road, Shenyang, Liaoning 110122, PR China.
State Key Laboratory of Frigid Zone Cardiovascular Disease, Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning 110016, PR China; College of Medicine and Biological Information Engineering, Northeastern University, 3-11 Wenhua Road, Shenyang, Liaoning 110819, PR China.
J Adv Res. 2025 Sep 13. doi: 10.1016/j.jare.2025.09.016.
Heart failure with preserved ejection fraction (HFpEF) is frequently complicated by atrial fibrillation (AF), but underlying molecular mechanisms remain poorly defined. Mitochondrial dysfunction drives ZBP1-mediated PANoptosis is crucial in understanding the progression of HFpEF-associated AF and exploring novel therapeutic avenues.
This study investigates the Z-DNA binding protein 1 (ZBP1) as a critical mediator linking mitochondrial dysfunction with PANoptosis by sensing mitochondrial Z-DNA (mtZ-DNA) in HFpEF-associated AF.
Variety of in vivo and in vitro experimental approaches were employed, majorly including HFpEF mouse model establishment, Histological staining, RNA sequencing, Western blotting, co-immunoprecipitation, Transmission electron microscopy (TEM) and confocal imaging.
In a "Two-hit" HFpEF mouse model, we observed increased AF susceptibility with prolonged modeling. Additionally, bioinformatics analysis and in vivo and in vitro studies highlighted progressive ZBP1-mediated PANoptosis accompanied by mitochondrial dysfunction in HFpEF atria. Inflammation and cardiomyocyte loss caused by PANoptosis contributed to atrial remodeling and AF. Also, NAD depletion in HFpEF cardiomyocytes downregulated mitochondrial topoisomerases (TOP3A and TOP1MT) and mitochondrial DNA (mtDNA) stress, promoting mtZ-DNA formation. ZBP1 sensed and stabilized Z-DNA via its Zα1 domain and recruited Receptor-Interacting Protein Kinases (RIPKs) and Caspase8 to assemble the PANoptosome and initiate PANoptosis. Silencing Zbp1 alleviated atrial remodeling and reduced AF vulnerability. Moreover, NAD supplementation suppressed Z-DNA formation and ZBP1 activation by improving mitochondrial dysfunction. These findings identify ZBP1 as a molecular bridge between mitochondrial dysfunction and PANoptosis, highlighting its central role in HFpEF-associated AF pathogenesis. Targeting this axis may provide a promising therapeutic strategy combatting AF in HFpEF.
These findings identify ZBP1 as a molecular bridge between mitochondrial dysfunction and PANoptosis by sensing mitochondrial Z-DNA, highlighting its central role in HFpEF-associated AF pathogenesis. Targeting this axis may provide a promising therapeutic strategy combatting AF in HFpEF.
射血分数保留的心力衰竭（HFpEF）常并发心房颤动（AF），但其潜在分子机制仍不清楚。线粒体功能障碍驱动ZBP1介导的全程序死亡对于理解HFpEF相关AF的进展及探索新的治疗途径至关重要。
本研究调查Z-DNA结合蛋白1（ZBP1）作为通过感知HFpEF相关AF中的线粒体Z-DNA（mtZ-DNA）将线粒体功能障碍与全程序死亡联系起来的关键介质。
采用了多种体内和体外实验方法，主要包括建立HFpEF小鼠模型、组织学染色、RNA测序、蛋白质印迹、免疫共沉淀、透射电子显微镜（TEM）和共聚焦成像。
在“双打击”HFpEF小鼠模型中，随着建模时间延长，我们观察到AF易感性增加。此外，生物信息学分析以及体内和体外研究突出了HFpEF心房中ZBP1介导的全程序死亡进展，同时伴有线粒体功能障碍。全程序死亡引起的炎症和心肌细胞损失导致心房重构和AF。此外，HFpEF心肌细胞中的NAD消耗下调了线粒体拓扑异构酶（TOP3A和TOP1MT）和线粒体DNA（mtDNA）应激，促进了mtZ-DNA的形成。ZBP1通过其Zα1结构域感知并稳定Z-DNA，并招募受体相互作用蛋白激酶（RIPKs）和半胱天冬酶8来组装全程序死亡小体并启动全程序死亡。沉默Zbp1可减轻心房重构并降低AF易感性。此外，补充NAD可通过改善线粒体功能障碍抑制Z-DNA形成和ZBP1激活。这些发现确定ZBP1是线粒体功能障碍与全程序死亡之间的分子桥梁，突出了其在HFpEF相关AF发病机制中的核心作用。靶向该轴可能提供一种有前景的治疗策略来对抗HFpEF中的AF。
这些发现确定ZBP1是通过感知线粒体Z-DNA在线粒体功能障碍与全程序死亡之间的分子桥梁，突出了其在HFpEF相关AF发病机制中的核心作用。靶向该轴可能提供一种有前景的治疗策略来对抗HFpEF中的AF。
