This study investigates the therapeutic potential of targeting histone deacetylase 6 (HDAC6) in heart failure with preserved ejection fraction (HFpEF) in mice. HFpEF is a common and severe form of heart failure, affecting over 50% of all heart failure cases, with limited treatment options. The study builds on previous research showing that HDAC6 inhibition improves outcomes in genetic cardiomyopathy models. Here, the researchers investigate HDAC6's role in HFpEF, given its shared mechanisms of inflammation and metabolism with the condition. Using a high-fat diet (HFD) combined with moderate transverse aortic constriction (mTAC), the researchers developed a mouse model that mimics key hemodynamic features of HFpEF. They found that inhibiting HDAC6 with TYA-018, a selective HDAC6 inhibitor, reversed established HFpEF and its associated symptoms in male mice. Additionally, mice lacking the Hdac6 gene showed delayed HFpEF progression and resistance to TYA-018's effects. The efficacy of TYA-018 was comparable to a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and the combination showed enhanced effects. Mechanistically, TYA-018 restored gene expression related to hypertrophy, fibrosis, and mitochondrial energy production in HFpEF heart tissues. It also inhibited activation of human cardiac fibroblasts and enhanced mitochondrial respiratory capacity in cardiomyocytes. The study found that HDAC6 plays a significant role in HFpEF pathophysiology, suggesting that HDAC6 inhibition could be a promising treatment for HFpEF. Genetic deletion of Hdac6 slowed HFpEF progression, and TYA-018 treatment improved diastolic function and cardiac relaxation in HFpEF mice. The study also found that TYA-018 had comparable efficacy to empagliflozin, an FDA-approved SGLT2 inhibitor, and that their combination had increased effects. TYA-018 improved mitochondrial function and metabolic transcripts in HFpEF mice, suggesting that HDAC6 inhibition may improve diastolic function by directly modulating myofilament- and calcium-associated proteins. The study highlights the potential of targeting HDAC6 as a treatment for HFpEF, either alone or in combination with current standard of care. The findings suggest that HDAC6 inhibition represents a promising new approach to address the unmet needs of HFpEF patients. The study also highlights the potential of TN-301, a chemical in the same series as TYA-018, which is currently in Phase 1 clinical testing for the treatment of HFpEF.This study investigates the therapeutic potential of targeting histone deacetylase 6 (HDAC6) in heart failure with preserved ejection fraction (HFpEF) in mice. HFpEF is a common and severe form of heart failure, affecting over 50% of all heart failure cases, with limited treatment options. The study builds on previous research showing that HDAC6 inhibition improves outcomes in genetic cardiomyopathy models. Here, the researchers investigate HDAC6's role in HFpEF, given its shared mechanisms of inflammation and metabolism with the condition. Using a high-fat diet (HFD) combined with moderate transverse aortic constriction (mTAC), the researchers developed a mouse model that mimics key hemodynamic features of HFpEF. They found that inhibiting HDAC6 with TYA-018, a selective HDAC6 inhibitor, reversed established HFpEF and its associated symptoms in male mice. Additionally, mice lacking the Hdac6 gene showed delayed HFpEF progression and resistance to TYA-018's effects. The efficacy of TYA-018 was comparable to a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and the combination showed enhanced effects. Mechanistically, TYA-018 restored gene expression related to hypertrophy, fibrosis, and mitochondrial energy production in HFpEF heart tissues. It also inhibited activation of human cardiac fibroblasts and enhanced mitochondrial respiratory capacity in cardiomyocytes. The study found that HDAC6 plays a significant role in HFpEF pathophysiology, suggesting that HDAC6 inhibition could be a promising treatment for HFpEF. Genetic deletion of Hdac6 slowed HFpEF progression, and TYA-018 treatment improved diastolic function and cardiac relaxation in HFpEF mice. The study also found that TYA-018 had comparable efficacy to empagliflozin, an FDA-approved SGLT2 inhibitor, and that their combination had increased effects. TYA-018 improved mitochondrial function and metabolic transcripts in HFpEF mice, suggesting that HDAC6 inhibition may improve diastolic function by directly modulating myofilament- and calcium-associated proteins. The study highlights the potential of targeting HDAC6 as a treatment for HFpEF, either alone or in combination with current standard of care. The findings suggest that HDAC6 inhibition represents a promising new approach to address the unmet needs of HFpEF patients. The study also highlights the potential of TN-301, a chemical in the same series as TYA-018, which is currently in Phase 1 clinical testing for the treatment of HFpEF.