Key result
RNF128 deletion improves cardiac performance in HFpEF by preventing PPARγ degradation and mitochondrial depletion.
Why the study?
HFpEF accounts for half of all heart failure cases and is closely linked to mitochondrial dysfunction and ubiquitin–proteasome system abnormalities.
Does genetic deletion of RNF128 improve mitochondrial function and cardiac performance in preclinical models of HFpEF?
Does genetic deletion of RNF128 improve mitochondrial function and cardiac performance in preclinical models of HFpEF?
RNF128 is identified as a novel regulator of HFpEF pathogenesis, suggesting that targeting the RNF128-PPARγ-VCP axis may provide a new therapeutic strategy for restoring mitochondrial bioenergetics.
Should not yet change HFpEF practice; hypothesis-generating for targeting the RNF128-PPARγ-VCP axis to restore mitochondrial bioenergetics.
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.
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Huang et al. (2026) studied Heart failure with preserved ejection fraction (HFpEF). Genetic deletion of RNF128 was evaluated on Mitochondrial function and cardiac performance. Genetic deletion of RNF128 restored mitochondrial function and improved cardiac performance in HFpEF by preventing PPARγ degradation and VCP-mediated mitochondrial depletion.
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