Objective To investigate the potential mechanisms underlying the therapeutic effects of Wendan decoction on adolescent depression by integrating network pharmacology and molecular docking techniques.

Methods Core active ingredients of Wendan decoction were collected and screened using databases including TCMSP, SymMap, PubChem, and SwissADME. Target predictions for these ingredients were performed using SwissTargetPrediction and SuperPred. Disease targets associated with adolescent depression were retrieved from the GeneCards database. The standard gene names of drug and disease targets were imported into Venny to identify intersection targets. Subsequently, core targets were screened using the STRING database and Cytoscape 3.10.0 software. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of the intersection targets were conducted using the DAVID database. Finally, molecular docking simulations were peroformed using AutoDock Tools-1.5.6, and the results were visualized using PyMOL 3.1.0 software.

Results A total of 134 active ingredients were identified from eight herbs: Pinellia ternata, Aurantii Fructus Immaturus, Bambusae Caulis in Taeniam, Citri Reticulatae Pericarpium, Poria, Glycyrrhizae Radix et Rhizoma, Zingiberis Rhizoma Recens and Jujubae Fructus. The major active ingredients included 5,7,4'-trimethylapigenin (5,7,4'-TMA), (+)-catechin, tetramethoxyluteolin, sinensetin, and 2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-6-(3-methylbut-2-enyl)chromone (6-PQC). Based on a probability threshold  > 0.2, 230 drug targets were selected, while 1,314 disease targets were identified based on the relevance score. This yielded 125 intersection targets, with 30 core targets highlighted, including peroxisome proliferator-activated receptor gamma (PPARG), signal transducer and activator of transcription 3 (STAT3), prostaglandin-endoperoxide synthase 2 (PTGS2), glycogen synthase kinase-3 beta (GSK3B), and matrix metalloproteinase 9 (MMP9). KEGG pathway enrichment analysis indicated that the therapeutic mechanism of Wendan decoction in treating depression primarily involves neuroactive ligand-receptor interaction, calcium signaling pathway, cancer pathways, chemical carcinogenesis-receptor activation, serotonergic synapse, and cAMP signaling pathway. Molecular docking validation demonstrated that key active ingredients of Wendan decoction, such as 5,7,4'-TMA, (+)-catechin, and 6-PQC, exhibited strong binding affinity to core targets including PPARG, GSK3B, and PTGS2.

Conclusion Wendan decoction alleviates adolescent depression through a "multi-component synergy and multi-target regulation" mechanism. It targets key proteins to ameliorate neuroinflammation, neurotransmitter imbalance, and neuroplasticity deficits. This study preliminarily elucidates the underlying mechanisms, providing a theoretical reference for clinical application; however, further in vitro and in vivo experiments are required for validation.

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