Abstract
Increased protein acetylation is frequently observed in the failing heart, including in hearts with heart failure with preserved ejection fraction (HFpEF). However, its role in the pathogenesis of HFpEF remains insufficiently investigated. Here, we found that HFpEF hearts displayed significantly protein hyperacetylation, which were predominantly localized to mitochondria and particularly enriched in fatty acid oxidation (FAO) pathway. Notably, Dlat, a pyruvate metabolism enzyme, was identified as the key transacetylase for mitochondrial protein hyperacetylation. Dlat overexpression enhanced FAO-related protein acetylation and exacerbated cardiac lipid metabolism disturbances, whereas Dlat knockdown effectively mitigated FAO inhibition and HFpEF phenotypes. Moreover, we demonstrated that Dlat directly triggers the acetylation of alpha subunit of mitochondrial trifunctional protein (HADHA) at the K728 site, thereby inactivating HADHA enzymatic activity. Our study provides a mechanistic basis linking protein hyperacetylation, FAO inhibition, and HFpEF development. Manipulating mitochondrial protein acetylation may offer potential strategies for therapeutic intervention of HFpEF.
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Data availability
There are no restrictions on data availability. All data supporting the findings of this study are available within the main text, supplementary information, and Source data. Further information and requests for resources and reagents should be directed to and will be fulfilled by the lead contact. Lipidomics data have been deposited in the Metabolights under the accession number MTBLS12919. Proteomics data and acetylation proteomics data have been deposited in the ProteomeXchange under the accession number PXD068270. Source data are provided with this paper.
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Acknowledgements
We appreciate all technicians in Innovation Center of Military Medicine of AFMU for their excellent technical assistance. This work was supported by grants from the National Natural Science Foundation of China: No. 82300443 (Lang Hu), No. 82400450 (Ying Wang) and No. 82470388 (Yan Li) and the Key Industrial Chain Projects of Shaanxi Province (Yan Li, 2024SF-ZDCYL-01-03).
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L.H., Y.L., and Y.W. conceptualized the study and designed the research. Y.W., D.G., J.Z., X.Y., C.W., J.G., Q.L., and P.C. performed the experiments. Y.W., D.G., J.Z., N.S., X.N., Y.L., Y.G., and L.H. contributed to the data analysis. Y.W., L.H., and D.G. drafted the article. L.H. and Y.L. revised and edited the article. All authors have read and approve the final article.
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Wang, Y., Guo, D., Zhu, J. et al. Pyruvate metabolism enzyme Dlat induces mitochondria protein hyperacetylation to limit fatty acid oxidation in the HFpEF heart. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70703-w
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DOI: https://doi.org/10.1038/s41467-026-70703-w
