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β-Hydroxybutyrate improves glymphatic system function and alleviates cerebral edema in mice after ischemic stroke

Acta Pharmacologica Sinica volume 47, pages 903–916 (2026)Cite this article

Abstract

Cerebral edema is a severe complication following ischemic stroke. Recent studies have highlighted the crucial role of the glymphatic system (GS) in the clearance of water and macromolecules. GS dysfunction involving the disorders of AQP4 polarization may be crucial in the pathophysiology of cerebral edema. β-Hydroxybutyrate (BHB), the main component of the ketone body, has been shown to alleviate neurological deficits by restoring GS function in subarachnoid hemorrhage models and to reduce Aβ deposition in Alzheimer’s disease models. In this study we investigated the effects of BHB on cerebral edema following ischemic stroke and its mechanisms. The mice were fed a ketogenic diet (KD) or a normal diet for 4 weeks before transient middle cerebral artery occlusion (MCAO). Alternatively, the mice received BHB (5 g·kg−1·d−1) or vehicle post-MCAO. By using brain section analysis, transcranial macroimaging, two-photon in vivo imaging and MRI, we demonstrated that both KD and BHB treatment significantly enhanced GS function under normal and MCAO conditions. BHB reduced cerebral edema and infarct volume post-MCAO. Notably, delayed BHB treatment initiated 10 h post-MCAO still improved GS function, but did not influence infarct volume. Furthermore, we revealed that BHB increased α1-syntrophin expression and H3K27ac levels in α1-syntrophin (Snta1) enhancer, restoring AQP4 polarization. In addition, BHB also reduced HDAC3 expression and elevated p300 expression. These results suggest that a KD and BHB treatment enhance GS function in mice and that BHB also mitigates brain edema after MCAO. The potentiation of GS function by BHB is likely mediated by the inhibition of HDAC3 activity and the increase in p300 activity, which upregulate α1-syntrophin expression and restore AQP4 polarization.

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Fig. 1: KD enhances GS function in normal and MCAO mice.
Fig. 2: BHB enhances GS function under physiological conditions.
Fig. 3: BHB alleviates GS function after MCAO.
Fig. 4: MRI results show improved GS influx function after MCAO.
Fig. 5: BHB alleviates brain edema and decreases infarct volume after MCAO.
Fig. 6: BHB partially restores AQP4 polarization after MCAO.
Fig. 7: BHB upregulates the expression of α1-syntrophin at the transcriptional level and enhances the colocalization of AQP4 and α1-syntrophin after MCAO.
Fig. 8: Epigenetic mechanism of BHB-upregulated α1-syntrophin expression.
Fig. 9: BHB alleviates brain edema following MCAO by enhancing GS function.

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Data availability

The datasets used and/or analyzed during this study are available from the corresponding authors upon reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82171345 & 82371467), the Guangdong Basic and Applied Basic Research Foundation (2024A1515012553 & 2023A1515110506), the China Postdoctoral Science Foundation (2024M751319), the Postdoctoral Fellowship Program of CPSF (GZC20231066), and the President Foundation of Nanfang Hospital, Southern Medical University (2023A005).

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  1. These authors contributed equally: Ming-jia Yu, Rui-qi Xiong, Jing-wen Wu, Yong-chuan Li

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  1. Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China

    Ming-jia Yu, Rui-qi Xiong, Jing-wen Wu, Yong-chuan Li, Jia-xin Xie, Hai-ping Zhou, Guan-yu Ye, Yuan Chang, Kai-bin Huang & Su-yue Pan

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Contributions

MJY, RQX, JXX, and YCL performed the animal experiments and analysis. MJY, JWW, HPZ, and JXX performed the molecular biology experiments and analyzed the results. MJY prepared the manuscript with input from all the authors. KBH, SYP, YC, and GYY revised the manuscript. KBH and SYP conceived and designed the studies. KBH, SYP, and YC provided the funding. All the authors read and approved the final version of the manuscript.

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Correspondence to Yuan Chang, Kai-bin Huang or Su-yue Pan.

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Yu, Mj., Xiong, Rq., Wu, Jw. et al. β-Hydroxybutyrate improves glymphatic system function and alleviates cerebral edema in mice after ischemic stroke. Acta Pharmacol Sin 47, 903–916 (2026). https://doi.org/10.1038/s41401-025-01706-4

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