Abstract: Systematic prediction of potential antidepressant compounds in Ganoderma lucidum and their target proteins as well as related signaling pathways was carried out employing network pharmacology and molecular docking. A mouse model of depression was then used to validate the antidepression efficacy and mechanism of action of the bioactive compounds. Our network-based analysis identified a “G. lucidum-bioactive compounds-intersection target-depression” interaction network, revealing 19 active constituents, including lucidone A, methyl lucidente Q, and cerevisterol, as well as 122 antidepression-related targets, such as serine/threonine-protein kinase 1 (AKT1), estrogen receptor 1 (ESR1), and interleukin-6 (IL-6). The core active compounds were predicted to exert their antidepression effects through various pathways, including the neuroactive ligand-receptor interaction pathway, neurodegeneration-related pathways, the phosphatidylinositol 3-kinase/protein kinase B (PI3K-AKT) signaling pathway, the cyclic adenosine monophosphate (cAMP) signaling pathway, and the mitogen-activated protein kinase (MAPK) signaling pathway. Molecular docking analysis demonstrated that the binding affinities of the core active compounds of G. lucidum, lucidone A, methyl lucidente Q, and cerevisterol, to key target proteins were all ≤ -7.0 kcal/mol. The results of network pharmacology corroborated that lucidone A had potential antidepression activity. Animal experiments further confirmed that lucidone A significantly alleviated depression-like behaviors in mice, ameliorated neuronal morphological damage in brain tissue, and reduced neurotransmitter concentrations. Moreover, lucidone A markedly suppressed the expression of pro-inflammatory mediators, including inducible iinducible nitric oxide synthase, cyclooxygenase-2, tumor necrosis factor-α, IL-6, IL-1β, and IL-17, thereby exerting its antidepressant effect. These findings provide a scientific foundation for the application of G. lucidum in functional food development.

Key words: Ganoderma lucidum; depression; network pharmacology; molecular docking; mechanism of action