RNF128 drives heart failure with preserved ejection fraction by impairing mitochondrial bioenergetics in cardiomyocytes

Heart failure with preserved ejection fraction (HFpEF) accounts for half of all heart failure cases and is closely linked to mitochondrial dysfunction and ubiquitin–proteasome system abnormalities. We found that the E3 ubiquitin ligase RNF128 is up-regulated in HFpEF myocardium, where it impairs mitochondrial respiration and promotes diastolic dysfunction. Mechanistically, RNF128 drives PPARγ degradation through ubiquitination and enhances VCP-mediated mitochondrial depletion, leading to the suppression of fatty acid oxidation. Genetic deletion of RNF128 reversed these effects, restoring mitochondrial function and improving cardiac performance. These findings identify RNF128 as a novel regulator of HFpEF pathogenesis and suggest that targeting the RNF128–PPARγ–VCP axis may provide a therapeutic strategy.