Abstract
Cognitive impairment is a known complication of metabolic dysfunction-associated steatotic liver disease (MASLD), and β-hydroxybutyrate (BHB), a ketone body providing alternative brain energy under metabolic stress, may exert neuroprotective effects. This study explored BHB’s role in MASLD-related cognitive impairment and its underlying mechanisms using a 20-week high-fat diet (HFD)-induced MASLD mouse model with cognitive dysfunction, comparing 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) knockout (KO), wild-type (WT), and exogenous BHB-supplemented mice. Key outcomes included hippocampal pathology, neuroinflammation, insulin resistance, amyloid-β (Aβ) deposition, tau phosphorylation, glucose/lipid homeostasis, and cognitive function. Results showed Hmgcs2 KO mice exhibited worse metabolic dysregulation (elevated triglycerides, cholesterol, hepatic lipid accumulation, impaired glucose tolerance, increased insulin, reduced BHB), cognitive decline (confirmed by Y-maze and novel object recognition tests), hippocampal p-Tau/Aβ aggregation, neuroinflammation (elevated iNOS, COX-2, IL-1β), and impaired IRS/PI3K/AKT/GSK3β signaling, whereas exogenous BHB supplementation alleviated these phenotypes. Collectively, reduced Hmgcs2 expression and BHB levels critically contribute to MASLD-induced cognitive impairment via cerebral insulin signaling disruption and neuroinflammation, highlighting BHB’s therapeutic potential.
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All data supporting the findings of this study are available within the paper and its Supplementary Information. Uncropped and unedited blot images are shown in Supplementary Figs. 5–11. Source data for the main figures are provided in Supplementary Data File 1. Additional data are available from the corresponding author upon request.
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Acknowledgements
This study was supported by the National Natural Science Foundation of China (grant number 82474318), the Jiangsu Administration of Traditional Chinese Medicine (grant number QN202411), the special fund for training outstanding young doctors in the second session of Jiangsu Province Hospital of Chinese Medicine (grant number 2024QB002), the project funded by Jiangsu Province Hospital of Chinese Medicine (grant number KKZX01), and the Hefei Municipal Health Science and Technology Project (grant number Hwk2025zd017).
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This study was conceptualized and designed by L.N., Q.X., and X.Z. L.N. performed the majority of the experiments, acquired and analyzed the data, and drafted the manuscript. J.S. and W.X. contributed some immunofluorescence and immunohistochemistry experiments, and analyzed some data. X.Y., G.W., and Y.W. assisted in the performance of animal experiments and reproduction of HMGCS2 KO mice. T.J., Y.C., and H.C. contributed to the performance of H&E stainings and immunoblotting. Q.X. revised the manuscript and provided critical feedback. X.Z. supervised the study, had full access to the data, and is responsible for the integrity of the data and accuracy of the analysis. All authors approved the final manuscript.
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Nie, L., Sun, J., Xu, W. et al. Hepatic HMGCS2-derived β-hydroxybutyrate attenuates hippocampal insulin resistance and neuroinflammation to promote MASLD-induced cognitive function. Commun Biol (2026). https://doi.org/10.1038/s42003-026-09513-1
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DOI: https://doi.org/10.1038/s42003-026-09513-1
