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β-hydroxybutyrate restores social deficits by suppressing HDAC9 in the ACC of Shank3B-deficient mice.

Overview

Authors: Erling Hu1,2, Jialong Li1,2, Chuchu Qi1,2, Junye Ge3, Yuanmeng Li4, Qian Xue1,2, Shengxi Wu1,2, Wenting Wang1,2
ORCID iDs: Erling Hu, Shengxi Wu, Wenting Wang
  1. Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, China
  2. The Shaanxi Province Key Laboratory of Brain Function Analysis and Modulation, Xi’an, China
  3. Guangdong Provincial Key Laboratory of Brain Function and Disease, Department of Physiology, School of Medicine, Shenzhen campus of Sun Yat-Sen University, Shenzhen, China
  4. School of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang, China
Institutions: Air Force Medical University (China); Sun Yat-sen University (China); Shaanxi University of Chinese Medicine (China)
Journal: EMBO molecular medicine, volume 18, issue 9, pages 3517-3539
Dates: received 27 February 2026; accepted 8 July 2026; published online 21 July 2026; in print September 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s44321-026-00491-9 · PMID 42481825 · PMCID PMC13562639 · OpenAlex W7169851053
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: mouse (organism), autism (population), cellular / molecular (subfield)
Methods: Statistics, Evoked potentials, Single-unit activity, calcium imaging
Keywords: Neuroscience
MeSH: 3-Hydroxybutyric Acid*, Autism Spectrum Disorder*, Gyrus Cinguli*, Histone Deacetylases*, Nerve Tissue Proteins*, Repressor Proteins*, Social Behavior*, Animals, Diet, Ketogenic, Male, Mice, Mice, Knockout, Microfilament Proteins, Neurons (* major topic)
Topic: Diet and metabolism studies (Physiology, Medicine), according to OpenAlex
Funding: MOST | National Natural Science Foundation of China (32394032,82221001, 82201704, 82271577); Science and Technology Innovation 2030 Project of China (2021ZD0201005); China Postdoctoral Science Foundation (2022M723883); Key Industry Innovation Chain of Shaanxi (2023-ZDLSF-47); Key Research and Development Projects of Shaanxi Province (2024SF-YBXM-033); Xijing Hospital (LHJJ24JH05)
Citations: not cited yet (Europe PMC); 45 references in the paper
Research resources: GraphPad Prism RRID:SCR_002798, Fiji software RRID:SCR_003070, Imaris software RRID:SCR_007370, pClamp RRID:SCR_11323

Abstract

Autism spectrum disorder (ASD) is characterized by core deficits in social behavior, yet effective interventions remain limited. Ketogenic diet (KD) shows behavioral benefits in ASD, but the underlying mechanisms remain unclear. Here, using Shank3B knockout (KO) mice, we found that KD ameliorates social deficits and induces systemic ketosis with marked elevation of β-hydroxybutyrate (BHB) in KO mice. Oral BHB alone recapitulates KD’s prosocial effects, restoring social interaction and neuronal activity in the anterior cingulate cortex (ACC). Mechanistically, we identified HDAC9 as a region- specific epigenetic target upregulated in ACC neurons of Shank3B KO mice and suppressed by BHB. HDAC9 overexpression in ACC neurons induces social and synaptic deficits, while class IIa HDAC inhibition phenocopies BHB effects. BHB also restores dendritic complexity, excitatory transmission, and AMPA receptor expression. These findings uncover a metabolite-driven epigenetic mechanism linking ketogenic metabolism to the rescue of social behavior via the ACC, and identify HDAC9 as a potential therapeutic target for ASD-related social deficits.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Data links

Data availability

The metabolomics data generated in this study have been deposited in the MetaboLights database under accession number MTBLS14381 and are publicly available at https://www.ebi.ac.uk/metabolights/MTBLS14381.

The source data of this paper are collected in the following database record: biostudies:S-SCDT-10_1038-S44321-026-00491-9 (https://www.ebi.ac.uk/biostudies/sourcedata/studies/S-SCDT-10_1038-S44321-026-00491-9).

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 8 authors, 1 keyword, 14 MeSH terms, 7 funders, 45 references, 4 RRIDs.

Cite

This paper

Hu, E., Li, J., Qi, C., Ge, J., Li, Y., Xue, Q., Wu, S., & Wang, W. (2026). β-hydroxybutyrate restores social deficits by suppressing HDAC9 in the ACC of Shank3B-deficient mice. EMBO molecular medicine, 18(9), 3517-3539. https://doi.org/10.1038/s44321-026-00491-9

BibTeX

@article{hu2026hydroxybutyrate,
author = {Hu, Erling and Li, Jialong and Qi, Chuchu and Ge, Junye and Li, Yuanmeng and Xue, Qian and Wu, Shengxi and Wang, Wenting},
title = {{β-hydroxybutyrate restores social deficits by suppressing HDAC9 in the ACC of Shank3B-deficient mice}},
journal = {EMBO molecular medicine},
year = {2026},
month = jul,
volume = {18},
number = {9},
pages = {3517--3539},
publisher = {Nature Publishing Group},
issn = {1757-4676},
doi = {10.1038/s44321-026-00491-9},
url = {https://doi.org/10.1038/s44321-026-00491-9},
pmid = {42481825},
pmcid = {PMC13562639}
}

RIS

TY - JOUR
AU - Hu, Erling
AU - Li, Jialong
AU - Qi, Chuchu
AU - Ge, Junye
AU - Li, Yuanmeng
AU - Xue, Qian
AU - Wu, Shengxi
AU - Wang, Wenting
TI - β-hydroxybutyrate restores social deficits by suppressing HDAC9 in the ACC of Shank3B-deficient mice
T2 - EMBO molecular medicine
J2 - EMBO Mol Med
PY - 2026
DA - 2026/07/21
VL - 18
IS - 9
SP - 3517
EP - 3539
SN - 1757-4676
PB - Nature Publishing Group
DO - 10.1038/s44321-026-00491-9
UR - https://doi.org/10.1038/s44321-026-00491-9
LA - en
ER -

CSL-JSON

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