• Dapagliflozin improves diastolic function and reduces cardiac hypertrophy, fibrosis, and apoptosis in a Dahl salt-sensitive rat model of HFpEF.
• Dapagliflozin restores mitochondrial structure and function and enhances mitochondrial respiratory capacity in cardiomyocytes.
• The SIRT1/PGC-1α/Mfn-2 signaling axis is identified as a critical pathway suppressed in HFpEF but reactivated by dapagliflozin.
• Activation of the SIRT1/PGC-1α/Mfn-2 pathway promotes mitochondrial biogenesis and dynamics, offering a potential therapeutic strategy for HFpEF.