Identification of key genes and enriched biological processes in diabetes-associated traumatic brain injury through weighted gene correlation network and bioinformatics analysis

Traumatic brain injury (TBI) is a significant cause of morbidity and mortality worldwide, with long-term neurological and psychological impacts. Recent studies have indicated that diabetes (T1DM) exacerbates the outcomes of TBI, leading to more severe cognitive deficits and increased risk of complications. This study investigated the underlying molecular mechanisms and potential therapeutic targets for T1DM-associated TBI. Four mRNA datasets (GSE4745, GSE125451, GSE173975, and GSE80174) downloaded from GEO repository were used in this study. Using limma, a total of 284 differentially expressed genes (DEGs) were identified in T1DM, of which 11 were upregulated and 9 were downregulated. GSEA showed that these DEGs were significantly enriched in cell communication, lipid metabolic process, and PPAR signaling. A total of 584 DEGs were identified in TBI, of which 186 were upregulated and 9 were downregulated. GSEA showed that these DEGs were mainly enriched in immune response-regulating signaling pathway. WGCNA identified 122 significant genes in TIDM-related modules and 368 significant genes in TBI-related module. GO and KEGG enrichment analysis showed that T1DM module genes were significantly correlated with lipid metabolic process and ribosome biogenesis, while TBI module genes were significantly correlated with inflammation and immune response, including leukocyte mediated immunity, lymphocyte mediated immunity, and cytokine mediated receptor activity. PPI network analysis of T1DM module genes identified 20 hub genes, including 14 ribosomal genes: Rpl23, Rps3a, Rps6, Rpl5, Rpl17, Rps24, Rpl23a, Rps4x, Rpl9, Rps15a14, Rpl30, Rpl31, Rps25, and Rps27a-2. The hub genes were primarily related to ribosome biogenesis and RNA post-transcriptional regulation. PPI network analysis of TBI module genes identified 20 hub genes: Ptprc, Tp53, Stat1, Stat3, Tyrobp, Itgad, Csf1r, Itgb2, Rac2, Icam1, Myd88, Cd44, Vav1, Aif1, C1qa, Laptm5, B2m, Fcer1g, and Lyn. The hub genes were primarily related to inflammatory mediators and immune response. Based on the overlap of T1DM module genes and TBI module genes, Cmklr1, Mgst1, and Plin2, were identified as key genes of T1DM-associated TBI. Functional enrichment analysis showed that they were primarily enriched in the cellular response to hydroperoxide, cytokine-mediated receptor signaling activity, regulation of sequestering of triglyceride, negative regulation of IL-12 production, and positive regulation of macrophage chemotaxis. Using Reactome, Cmklr1, Mgst1, and Plin2 were related to cytokine signaling activity, neutrophil degranulation, and lipid storage, respectively. We concluded that Lipid droplet dysregulation and Neuroinflammation are the potential molecular mechanisms of T1DM-associated TBI. Cmklr1, Mgst1, and Plin2 are positively correlated with T1DM-associated TBI and may be important biomarkers and potential treatment targets for diabetic TBI.