Download PDF
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.
Subjects
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
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
Authors
- Jingxuan WangView author publications
Search author on:PubMed Google Scholar
- Lizhi DaiView author publications
Search author on:PubMed Google Scholar
- Tong YuView author publications
Search author on:PubMed Google Scholar
- Zheyuan CaoView author publications
Search author on:PubMed Google Scholar
- Youchong LiView author publications
Search author on:PubMed Google Scholar
- Yuhao ZhangView author publications
Search author on:PubMed Google Scholar
- Tao LiuView author publications
Search author on:PubMed Google Scholar
- Hongbin WangView author publications
Search author on:PubMed Google Scholar
- Jianhua XiaoView author publications
Search author on:PubMed Google Scholar
Ethics declarations
Competing interests
The authors declare no competing interests
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations
Supplementary information
Supplementary Information (download PDF )
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
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
