Core Viewpoint - The study highlights the role of hepatic acetyl-CoA metabolism in modulating neuroinflammation and susceptibility to depression through acetate signaling [3][5][7]. Group 1: Research Findings - Chronic stress induces a metabolic shift in the liver from glucose metabolism to acetate metabolism [5]. - The hydrolysis of acetyl-CoA in the liver is a key source of circulating acetate [5]. - The enzyme ACOT12 catalyzes the hydrolysis of acetyl-CoA in the liver, sending signals to the brain to help alleviate stress [5]. - Acetate exerts antidepressant-like effects by enhancing PD-L1 signaling [5]. Group 2: Mechanism of Action - The hydrolysis of acetyl-CoA in the liver is a critical component of the liver-brain axis that regulates susceptibility to depression [7]. - Overexpression of ACOT12 in the liver increases acetate output, promoting histone acetylation in the ventral hippocampus, which alleviates depressive-like behaviors [4][5].