Identification of potential Mitogen-Activated Protein Kinase-related key genes and regulation networks in molecular subtypes of major depressive disorder

Abstract

BackgroundMajor depressive disorder (MDD) is a heterogeneous and prevalent mental disorder associated with increased morbidity, disability, and mortality. However, its underlying mechanisms remain unclear.Materials and methodsAll analyses were conducted based on integrated samples from the GEO database. Differential expression analysis, unsupervised consensus clustering analysis, enrichment analysis, and regulation network analysis were performed.ResultsMitogen-activated protein kinase (MAPK) signaling pathway was identified as an associated pathway in the development of MDD. From transcriptional signatures, we classified the MDD patients into two subgroups using unsupervised clustering and revealed 13 differential expression genes between subgroups, which indicates the probably relative complications. We further illustrated potential molecular mechanisms of MDD, including dysregulation in the neurotrophin signaling pathway, peptidyl-serine phosphorylation, and endocrine resistance. Moreover, we identified hub genes, including MAPK8, TP53, and HRAS in the maintenance of MDD. Furthermore, we demonstrated that the axis of miRNAs-TFs-HRAS/TP53/MAPK8 may play a critical role in MDD.ConclusionTaken together, we demonstrated an overview of MAPK-related key genes in MDD, determined two molecular subtypes, and identified the key genes and core network that may contribute to the procession of MDD.

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“…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 ].…”

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“…In the context of obese patients with concurrent depression, TP53 emerges as a molecular indicator of inflammation-associated depression 22,23 . Furthermore, aberrant TP53 gene expression is implicated as a potential etiological factor in depression, which is intricately linked to the HRAS/TP53/MAPK8 axis 24,25 . Clinical investigations have demonstrated that heightened HSP90AA1 activity within the anterior cingulate cortex of individuals with depression may impede tissue remodeling and immune responses in depression patients [26][27][28] .…”

“…Subsequently, 100 μL of cell suspension was added to each well. Following a 12 hours incubation period, varying concentrations of Cort (0, 25, 50, 100 and 200 μg/mL) were introduced, and the cells were incubated in a 37°C and 5% CO2 environment for specified durations (12,24,48 and 72 hours). The cellular activity of HT22 cells was assessed using the CCK-8 assay.…”

“…Figure4LBT reduce Cort-induced HT22 cells damage A. HT22 cells were subjected to varying concentrations of Cort (0, 25, 50, 100 and 200 μg/mL) for different durations(12,24, 48, and 72 hours) to assess cell viability using the CCK-8 assay (n = 3). B.…”

“…Following 24 hours exposure to 100 μg/mL Cort, HT22 cells were treated with different concentrations of LBT (0.125, 0.25 and 0.5 μg/mL), and cell viability was evaluated using the cck-8 assay (n = 3). C. HT22 cells were treated with different concentrations of LBT (0, 0.125, 0.25, 0.5 and 1.0 μg/mL)) for varying time periods(12,24, 48, and 72 hours) to determine cell viability through the CCK-8 assay (n = 3). D. Cytotoxicity was detected using the intracellular LDH release assay (n = 3).…”