Gasdermin D Inhibition Attenuates Mitochondrial Damage and Cardiomyocyte Pyroptosis in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) represents the most prevalent subtype of heart failure globally, with its underlying pathogenesis remaining incompletely elucidated. Pyroptosis and mitochondrial dysfunction have been implicated in HFpEF progression. In addition, gasdermin D (GSDMD) has been shown to mediate both mitochondrial dysfunction and pyroptosis, yet the specific regulatory mechanisms involved in HFpEF remain to be elucidated. In this study, we found that HFpEF mouse models exhibited elevated blood glucose and blood pressure, impaired diastolic cardiac function, upregulated serum NT-proBNP, increased heart weight-to-tibia length (HW/TL) ratio, reduced exercise tolerance, obvious myocardial structural damage, excessive mitochondrial ROS accumulation, increased mitochondrial GSDMD-N expression, mitochondrial morphological abnormalities, and activated myocardial pyroptosis pathway. Treatment with GI-Y2 significantly ameliorated these changes. Collectively, GSDMD contributes to HFpEF progression by promoting mitochondrial damage and cardiomyocyte pyroptosis.