Gene expression profiling of sex-specific differences in systemic lupus erythematosus morbidity

• By comparing results of functional enrichment analyses from male SLE versus male healthy controls comparison group and female SLE versus female healthy controls comparison group, we observed a far greater number of differentially expressed genes in females, particularly those related to innate/antiviral response, NK-cell-mediated cytotoxicity, antigen processing and presentation, and cell cycle regulation. • In contrast, male patients primarily showed T-cell receptor signaling abnormalities. • Protein–protein interaction network analysis also supported these findings, identifying additional cytotoxic and NK-cell–related hubs in females but predominantly T-cell–related hubs in males. • These findings suggest that, while Tcell dysregulation is the major cause of SLE in both sexes, women may experience broader immunological disruptions other than T cell-related activities that heighten disease prevalence and severity. Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by markedly higher prevalence and differential severity in women. SLE is less prevalent in males; however, male patients frequently exhibit slightly more severe cardiovascular and renal manifestations. This study examined the gene expression profiles of male and female patients with systemic lupus erythematosus (SLE) to identify both shared and divergent patterns, thereby providing insight into the molecular mechanisms underlying sex-based differences in SLE morbidity. Using the publicly available transcriptomic dataset GSE82221, derived from peripheral blood mononuclear cells of patients with systemic lupus erythematosus (SLE), we performed differential gene expression analysis, functional enrichment analysis (Gene Ontology and KEGG pathways), protein–protein interaction analysis, and integrated gene network analysis. Comparative functional enrichment analyses of male SLE versus male healthy controls and female SLE versus female healthy controls revealed a substantially greater number of differentially expressed genes in females, particularly those associated with innate antiviral responses, NK cell–mediated cytotoxicity, antigen processing and presentation, and cell cycle regulation. In contrast, male patients predominantly exhibited abnormalities in T-cell receptor signaling pathways. Protein–protein interaction network analysis further corroborated these findings, revealing additional cytotoxic and NK cell–associated hubs in females, whereas males predominantly exhibited T cell–related hubs. These findings suggest that although T-cell dysregulation represents a central pathogenic mechanism in systemic lupus erythematosus (SLE) across both sexes, women may experience broader immunological perturbations beyond T cell–related pathways, contributing to heightened disease prevalence and differential manifestations of the disease. Future studies incorporating larger, sex-balanced cohorts and multi-omics approaches are needed to elucidate sexually divergent mechanisms and to develop personalized treatment strategies for systemic lupus erythematosus (SLE).