Integrative transcriptomic and immune-genomic analysis identifies oxidative-stress-associated immune signatures and SPTLC1, PTGES3, and HLA-G as candidate hub genes in chronic insomnia

Abstract Background Chronic insomnia involves peripheral immune dysregulation, yet its dominant perturbation pathways, candidate immune-genomic markers, and the relative contributions of germline genetic versus non-genetic regulation remain unclear. We analyzed the GSE208668 peripheral blood mononuclear cell microarray dataset comprising 17 patients with chronic insomnia and 25 controls through an integrative transcriptomic and immune-genomic pipeline. Results Oxidative-stress- and immune-related pathway alterations were characterized using pathway scoring, differential expression analysis, weighted gene co-expression network analysis, machine-learning-based feature prioritization, immune-cell deconvolution, cross-cohort transcriptomic comparison, SMR/HEIDI analysis, and drug–gene interaction screening. The insomnia-associated co-expression module was enriched for immune regulation, inflammatory signaling, antigen presentation, and stress-response processes. Machine-learning prioritization highlighted a set of candidate genes, among which SPTLC1, PTGES3, and HLA-G emerged as core consensus hub genes. Within the discovery dataset, these genes showed strong separation between insomnia and control samples. Internal classification analysis based on the three-gene model showed complete separation in the discovery cohort; however, this finding should be interpreted as internal separability rather than clinical diagnostic validity. SMR/HEIDI analysis did not identify Bonferroni-significant cis-eQTL-mediated germline regulatory evidence for the testable candidate genes, suggesting that the observed transcriptional alterations were not readily explained by detectable germline regulatory effects under the current data and analysis framework. Drug–gene interaction screening further identified potentially actionable gene–drug links for hypothesis generation. Conclusions This study provides an integrative transcriptomic and immune-genomic characterization of chronic insomnia and identifies SPTLC1, PTGES3, and HLA-G as candidate hub genes associated with oxidative-stress-related immune signatures. These findings are exploratory and require confirmation in larger independent cohorts and experimental studies before clinical translation.