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  3. Hepatic acetyl-CoA metabolism modulates neuroinflammation and depression susceptibility via acetate

Hepatic acetyl-CoA metabolism modulates neuroinflammation and depression susceptibility via acetate

  • Cell Metab. 2025 Sep 23:S1550-4131(25)00383-3. doi: 10.1016/j.cmet.2025.08.010.
Yu Cao 1,  Yang Zhao 1,  Tan Deng 1,  Qigang Zhou 2,  Gang Hu 2,  Zhuang-Li Hu 3,  Yan-Yi Jiang 1,  Xiao-Han Yang 1,  Fang Wang 4,  Peng-Fei Wu 5,  Jian-Guo Chen 6
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Basic Medicine and Department of Pharmacy, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
  • 2 Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China.
  • 3 Department of Pharmacology, School of Basic Medicine and Department of Pharmacy, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China; The Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, China.
  • 4 Department of Pharmacology, School of Basic Medicine and Department of Pharmacy, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China; The Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, China. Electronic address: wangfanghust@hust.edu.cn.
  • 5 Department of Pharmacology, School of Basic Medicine and Department of Pharmacy, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China; The Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, China. Electronic address: wupengfeitjmu@hust.edu.cn.
  • 6 Department of Pharmacology, School of Basic Medicine and Department of Pharmacy, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China; The Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, China; Hubei Shizhen Laboratory, Wuhan 430030, China. Electronic address: chenjg@hust.edu.cn.
PMID: 40992374 DOI: 10.1016/j.cmet.2025.08.010
Abstract

Extensive research highlights impaired brain energy metabolism in neuropsychiatric disorders, whereas much less is known about the role of the peripheral metabolic state. The liver is the metabolic hub, and herein we demonstrate that hepatic hydrolysis of acetyl-coenzyme A, a central metabolic intermediate, signals the brain and helps buffer stress. Using a chronic social defeat stress paradigm in male mice, we observed a hepatic glucose-to-acetate metabolic switch, followed by a glucocorticoid-repressed transcription of the acetyl-coenzyme A hydrolase, acetyl-coenzyme A thioesterase 12, to confer stress vulnerability. Hepatic overexpression of acetyl-coenzyme A thioesterase 12 alleviated depression-like phenotypes via increasing acetate output to promote histone acetylation in the ventral hippocampus, which bolstered the expression of programmed cell death ligand 1 in astrocytes, limiting neuroinflammation and rescuing inhibitory synaptic transmission dysfunction. Our findings demonstrate that hepatic acetyl-coenzyme A hydrolysis serves as a key liver-brain axis component that regulates depression susceptibility.

Keywords

acetate; acetyl-coenzyme A; depression; liver-brain communication; stress.

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