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NAT10 regulates heart development and function by maintaining the expression of genes related to fatty acid β-oxidation and heart contraction

Cell Death & Differentiation (2025)Cite this article

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Abstract

Energy metabolism is crucial for heart development and function, and dysregulation of this process can lead to heart failure. However, the molecular mechanisms underlying these processes, particularly the role of RNA-binding proteins (RBPs)-mediated posttranscriptional regulation, remain largely unclear. We identified N-acetyltransferase 10 (NAT10) as a key regulator of heart function and cardiac diseases. NAT10 is crucial for heart development, and its dysregulation is associated with heart failure. Cardiac-specific deletion of Nat10 leads to dilated cardiomyopathy, heart failure, and postnatal death by downregulating genes related to fatty acid β-oxidation and heart contraction. Adult-onset knockout Nat10 also results in dilated cardiomyopathy and heart failure. NAT10-deficient hiPSC-CMs also showed impaired calcium transients during contraction. Restoration of NAT10(WT) and NAT10(G641E) (an N-acetyltransferase-inactive mutation), but not NAT10(K290A) (a loss-of-RNA-binding activity mutation), fully rescues the dilated cardiomyopathy, heart failure, and postnatal death phenotypes in Nat10-CKO mice by restoring expression of genes involved in fatty acid β-oxidation and heart contraction. The RNA-binding activity of NAT10 is essential for maintaining the expression of these genes. These findings demonstrate that NAT10 plays a critical role in heart development and function by maintaining the expression of genes related to fatty acid β-oxidation and heart contraction, highlighting its importance in maintaining heart health.

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Fig. 1: NAT10 is associated with heart failure and cardiomyocyte-specific deletion of Nat10 causes dilated cardiomyopathy, heart failure and postnatal death in mice.
Fig. 2: Adult-onset cardiomyocyte-specific deletion of Nat10 causes dilated cardiomyopathy and heart failure.
Fig. 3: Cardiomyocyte-specific deletion of Nat10 greatly alters gene expression profile in the heart.
Fig. 4: The RNA-binding, but not acetyltransferase, activity is essential for NAT10 to promote heart development and maintain heart function.
Fig. 5: The RNA binding, but not acetyltransferase, activity is essential for NAT10 to maintain expression of fatty acid β-oxidation- and heart contraction-related genes.
Fig. 6: NAT10 is associated with transcripts related to fatty acid β-oxidation and heart contraction.
Fig. 7: Cardiomyocyte-specific deletion of Nat10 does not regulate translational efficiency.
Fig. 8: NAT10 regulates the mRNA stability for genes related to fatty acid β-oxidation and heart contraction.

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Data availability

All data are available in the main text or the supplementary materials. The RNA-seq data that support the findings of this study have been deposited in GEO under accession codes GSE274007, GSE274008, and GSE295332 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?&acc=GSE274007; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE274008; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE295332). The RIP-seq data that support the findings of this study have been deposited in GEO under accession codes GSE274009 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE274009). The Ribo-seq data that support the findings of this study have been deposited in GEO under accession codes GSE295333 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE295333). All biological materials used are readily available from the authors or from standard commercial sources.

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Acknowledgements

We thank Novogene and DIATRE Biotechnology for assistance in RNA-seq, RIP-seq and Ribo-seq experiments, respectively.

Funding

This study was supported by the National Natural Science Foundation of China Grants (82525015, 32371198 and 82370861), the Heilongjiang Chunyan Team (CYCX24020), Frontiers Science Center for Matter Behave in Space Environment and the Fundamental Research Funds for the Central Universities (HIT.OCEF.2025001), Doctor of excellence program (DEP) at the First Hospital of Jilin University (JDYY-DEP-2024040).

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Author notes

  1. These authors contributed equally: Lei Shi, Meiwei Zhang, Hao Yang.

Authors and Affiliations

  1. Department of Cardiology, Department of Endocrinology & Metabolism, The First Hospital of Jilin University, Changchun, China

    Lei Shi, Meiwei Zhang, Zhiguo Zhang & Zhuo Li

  2. HIT Center for Life Sciences, School of Life Science and Technology, School of Medicine and Health, State Key Laboratory of Matter Behaviors in Space Environment, Frontier Science Center for Interaction between Space Environment and Matter, Zhengzhou Research Institute, Harbin Institute of Technology, Harbin, China

    Lei Shi, Yanshuo Chu, Minghui Gao & Zheng Chen

  3. Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen, China

    Hao Yang, Siyi He & Joe Z. Zhang

  4. NHC Key Laboratory of Cell Transplantation, First Affiliated Hospital of Harbin Medical University, Harbin, China

    Xinzhi Li

  5. State Key Laboratory of Space Medicine, China Astronaut Research and Training Center, Beijing, China

    Zheng Chen

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Contributions

LS performed most of the experiments and analyzed the data. MZ performed the experiments. HY, SH and JZ performed the iPSC-CM experiments and analyzed the data. XL performed RIP-seq experiments. YC helped to analyze the RNA-seq data. MG provided Nat10flox/flox mice and reviewed this study. ZZ and ZL guided this study. ZC conceived and designed the project, researched data, and wrote the manuscript. All authors give their consent for the publication of the above manuscript.

Corresponding authors

Correspondence to Minghui Gao, Zhiguo Zhang, Joe Z. Zhang, Zhuo Li or Zheng Chen.

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This study was approved by the Institutional Animal Care and Use Committee or Animal Experimental Ethics Committee of Harbin Institute of Technology (HIT/IACUC-2022066). All authors complied with all relevant ethical regulations for animal testing and research.

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Shi, L., Zhang, M., Yang, H. et al. NAT10 regulates heart development and function by maintaining the expression of genes related to fatty acid β-oxidation and heart contraction. Cell Death Differ (2025). https://doi.org/10.1038/s41418-025-01577-6

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