Why the study?
Heart failure with preserved ejection fraction is frequently complicated by atrial fibrillation, but the underlying molecular mechanisms remain poorly defined.
Does targeting ZBP1 and mitochondrial dysfunction prevent atrial fibrillation in a model of HFpEF?
Does targeting ZBP1 and mitochondrial dysfunction prevent atrial fibrillation in a model of HFpEF?
Mitochondrial dysfunction drives ZBP1-mediated PANoptosis to increase susceptibility to atrial fibrillation in a HFpEF model, identifying ZBP1 as a potential therapeutic target.
INTRODUCTION: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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Duan et al. (2025) studied this question.
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