Environmental factors have been reported to play a significant role in the onset of MDD, as the majority of cases are believed to occur randomly [37]. Epidemiological studies have suggested a possible association between exposure to pesticides and the development of MDD [5]. To better understand the molecular mechanisms underlying Gly-induced MDD, bioinformatics algorithms were used to explore aberrantly expressed mRNAs between MDD patients and controls, which identified 1216 DEGs (776 upregulated and 440 downregulated) from the GSE76826 dataset. Network pharmacology predicted 43 potential targets of Gly associated with the induction of MDD (32 upregulated and 11 downregulated). GO and KEGG analyses were performed to investigate the biological characteristics of these potential targets and six hub targets (CD40, FOXO3, FOS, IL6, TP53, and VEGFA) were identified using molecular docking.

CD40 is a transmembrane protein and a member of the tumor necrosis factor receptor superfamily that plays a crucial role in the initiation and maintenance of inflammatory reactions [16]. CD40-mediated aberrant neuroinflammation can increase permeability of the blood–brain barrier and subsequently damage neurons and glial cells [30]. A previous study suggested that newly diagnosed depression is associated with increased expression of platelet-derived CD40 [29]. In addition, depression-like behavior was associated with abnormal microglial expression of CD40 in a rat model of Alzheimer’s disease [17]. Gly has been demonstrated to induce death of human neuroblastoma SH-SY5Y cells through upregulation of CD40 expression [27]. Therefore, CD40 and related inflammatory signaling pathways are potential targets for the treatment of Gly-induced MDD.

FOXO3 is a crucial transcription factor that regulates various gene networks associated with cellular metabolism that contribute to various physiological and pathological processes [8], and plays a critical role in oxidative stress-induced neuronal death [39]. Recent studies have indicated an association between MDD and selective and persistent death of hippocampal neurons [23]. Although the role of FOXO3 in MDD remains unclear, a prior epidemiological study suggested that genetic variants of FOXO3 may be associated with depressive symptoms in older adults [26]. It has been reported that Gly exposure induced proliferation of breast cancer cells through upregulation of FOXO3 mRNA expression [33]. Collectively, these findings suggest that FOXO3 may play a key role in Gly-induced MDD, although further investigations are needed to clarify the underlying mechanisms.

FOS is a transcription factor that is rapidly and transiently activated [15]. Hence, numerous studies have advocated the use of FOS as an indicator of stimulus-triggered modifications in brain function [15]. Many studies have reported altered expression of FOS in models of depression. Blue light deprivation is reported to produce a depression-like response in Mongolian gerbils accompanied by decreased FOS expression in brain tissues [20]. Another study reported that rice wine can potentially reduce stress-induced depression-like behaviors and FOS expression in rats [28]. In addition, FOS was associated with Gly-induced hematotoxicity via dysregulation of hematopoietic stem cell function [19] and Gly-induced anxiety and depression-like behavior in mice was accompanied by increased FOS expression in brain tissues [1]. However, it remains unclear whether FOS is a key molecule in Gly-induced MDD.

Increased expression of the cytokine IL6, in both peripheral and central systems, is believed to play a vital role in stress reactions and depressive disorders, especially as a comorbidity with physical illnesses [13, 40, 41]. Elevated IL6 activity can potentially induce depression via stimulation of the hypothalamic–pituitary–adrenal axis or modulation of neurotransmitter metabolism [36]. Hence, manipulation of IL-6 activity could benefit individuals with MDD and inflammatory characteristics [36]. Perinatal exposure to Gly significantly increased IL6 expression and caused liver damage in rat offspring [31]. In addition, Gly induced an inflammatory response mediated by elevated IL6 and altered the microbial composition in the rat intestine [34]. Taken together, these findings suggest that IL6 is a potential key molecule in the onset of Gly-induced MDD.

TP53 acts as a transcription factor that regulates the expression of almost 500 target genes that participate in various cellular processes, including cell death, the cell cycle, cell senescence, DNA repair, and metabolism [35]. In addition, TP53 is involved in regulation of the mitogen-activated protein kinase signaling pathway, which plays an important role in the development and progression of MDD [12]. Epidemiological studies have shown that genetic polymorphisms of TP53 are strongly associated with MDD and the minor allele 72 C may be a protective factor against MDD [25]. Gly has been reported to influence TP53 expression in human peripheral blood mononuclear cells by increasing methylation of the TP53 promoter [38]. Recent research of TP53 has mainly focused on tumor formation and development. However, the results of the present study found that TP53 may play a key role in Gly-induced MDD. Therefore, further studies are warranted to investigate the underlying mechanisms.

VEGF is elevated in damaged vessels and neurons, abnormal branching, and chronic inflammatory conditions, such as cardiovascular disease and depression [2, 10]. In a previous study, serum VEGFA mRNA and protein levels were significantly elevated in patients with MDD, suggesting a potentially important role in the pathogenesis of depression [7]. Another study found increased mRNA levels of VEGFA in peripheral blood cells and serum in patients with recurrent depression as compared to healthy controls, and suggested that VEGFA gene polymorphism could be a prognostic factor for the development of recurrent depression [18]. Furthermore, it has been reported that exposure to Gly during pregnancy reduces placental vascular density and cell proliferation via interference with VEGFA expression and subsequent impaired barrier function and nutrient transport in the placenta of newborn piglets [3]. These findings combined with the results of the present study indicate that VEGFA may play an important role in the onset of Gly-induced MDD.