Ketogenic diet induces cardiac changes via the OHB-Ffar3-Hopx/ACTC1 regulatory pathway in growing mice

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Abstract

The ketogenic diet (KD), a high-fat, low-carbohydrate dietary regimen widely used for drug-resistant epilepsy and weight management, has been increasingly applied in adolescents. However, its long-term effects on juvenile cardiac development and functional homeostasis remain poorly understood. Here, juvenile mice (postnatal day 28–84) were fed a KD, and the underlying mechanisms were further investigated in β-hydroxybutyrate (OHB)-treated H9C2 cardiomyocytes. KD induced sustained ketosis, reduced body weight gain, and promoted a smaller cardiac phenotype accompanied by progressive alterations in ventricular functional parameters, including decreased LVEF/LVFS, septal thinning, and elevated BNP levels. Histological analyses revealed myocardial disorganization, myofibrillar disruption, mitochondrial abnormalities, and reduced cardiomyocyte area, together with decreased expression of proteins involved in cardiac contraction and calcium handling. Transcriptomic analysis identified Hopx as a key downregulated gene. Mechanistically, OHB exposure was associated with increased Ffar3 expression and reduced Hopx expression, while HOPX was found to interact with ACTC1. Hopx silencing recapitulated the OHB-induced alterations, whereas Hopx overexpression partially alleviated these effects. Collectively, long-term KD/OHB exposure impairs juvenile cardiac development and functional homeostasis through a candidate OHB-Ffar3-Hopx/ACTC1 regulatory pathway, highlighting potential cardiac risks associated with prolonged KD exposure during postnatal development.

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Acknowledgements

This work was supported by grants from the National Key Research and Development Program of China (Grant No. 2023YFD1801100). All figures created with BioRender in this manuscript have obtained Publication License from BioRender.com. We express our gratitude to BioRender.com for providing the illustration rem

Authors and Affiliations

1. Key Laboratory for Prevention and Control of Common Animal Diseases in General Higher Education Institutions of Heilongjiang Province, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China

   Jingxuan Wang, Lizhi Dai, Tong Yu, Zheyuan Cao, Youchong Li, Yuhao Zhang, Tao Liu, Hongbin Wang & Jianhua Xiao

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1. Jingxuan WangView author publications

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2. Lizhi DaiView author publications

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3. Tong YuView author publications

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4. Zheyuan CaoView author publications

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5. Youchong LiView author publications

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6. Yuhao ZhangView author publications

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7. Tao LiuView author publications

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8. Hongbin WangView author publications

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9. Jianhua XiaoView author publications

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Wang, J., Dai, L., Yu, T. et al. Ketogenic diet induces cardiac changes
npj Sci Food (2026). https://doi.org/10.1038/s41538-026-01055-4

• Received:04 March 2026

• Accepted:29 July 2026

• Published:08 August 2026

• DOI
  :https://doi.org/10.1038/s41538-026-01055-4