Exploring the mechanism of Yin Huo decoction in PCPA-induced depression mice: a metabolomics and network pharmacology approach.

Introduction: Depression is a prevalent neuropsychiatric disorder, and traditional Chinese medicine formulations such as Yin Huo Decoction (YHD) have shown potential antidepressant effects, yet their underlying mechanisms remain incompletely elucidated. This study aimed to investigate the therapeutic effects and molecular mechanisms of YHD in a PCPA-induced depression model in mice. Methods: PCPA-induced depressive-like mice were treated with YHD, and changes in body weight, sucrose preference, and behavioral performance in the forced swim and tail suspension tests were assessed. Hippocampal neuron structure and Nissl body integrity were examined, and brain serotonin (5-HT) levels were quantified. Liquid Chromatograph Mass Spectrometer (LC-MS)-based metabolomic profiling was performed on serum, urine, and brain tissue to identify metabolic disturbances, while network pharmacology analysis was used to explore the intersection of YHD targets and depression-related pathways. Pathway enrichment analysis was conducted to clarify key regulatory pathways. Results: YHD treatment significantly improved body weight, sucrose preference, and depressive-like behaviors in PCPA-induced mice, and preserved hippocampal neuron structure and Nissl body integrity-effects comparable to fluoxetine. YHD also restored reduced brain 5-HT levels in PCPA model mice. Metabolomic analysis revealed distinct metabolic perturbations in the PCPA model (e.g., in tryptophan and riboflavin metabolism), which were largely reversed by YHD. Network pharmacology identified 156 intersecting targets between YHD and depression-related pathways, primarily involved in neuroactive ligand-receptor interactions, dopaminergic synapses, and inflammatory processes (e.g., TNF signaling and cytokine production). Key targets including AKT1, TNF, IL-6, and EGFR were identified as central to YHD's action. Discussion: YHD alleviates PCPA-induced depression-like behaviors in mice by modulating 5-HT levels, correcting metabolic imbalances in tryptophan and riboflavin pathways, and regulating neuroinflammation, neurotransmitter systems, and cellular signaling via targets such as AKT1 and TNF. These findings provide a comprehensive mechanistic understanding of YHD's antidepressant effects, supporting its potential as a therapeutic agent for depression.