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.

华中科技大学陈建国团队揭示肝脏乙酰辅酶A代谢通过乙酸盐调节神经炎症和抑郁易感性|膜片钳|慢性社交挫败应激

Cell Metab,2025 Sep 23:S1550-4131(25)00383-3. doi: 10.1016/j.cmet.2025.08.010.