Mitochondrial dysfunction drives ZBP1-mediated PANoptosis to increase the susceptibility of heart failure with preserved ejection fraction-associated atrial fibrillation

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.