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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.