Age- and sex-dependent transcriptomic network alterations in sepsis

Sepsis arises from a dysregulated immune response to infection, causing systemic inflammation and high mortality. Its nonspecific symptoms and complex molecular mechanisms make early diagnosis and therapeutic development challenging. The contribution of host factors to this heterogeneity is not fully understood. We investigated whether baseline gene co-expression networks are preserved or reorganized in sepsis and whether age and sex influence these networks by analyzing RNA-seq data from Peripheral Blood Mononuclear Cells (PBMCs) of healthy Romanian individuals and sepsis patients. Sixteen co-expression modules were identified in healthy controls. Most were preserved in sepsis, but four exhibited disrupted organization, indicating selective network reprogramming. Notably, the green module was strongly associated with age, sex, and sepsis. Within this module, 13 age-associated and 20 sex-associated hub genes were identified. Individual hub genes showed modest discriminative ability, whereas a multigene model achieved high accuracy (AUC = 0.988). Transcription factor motif enrichment highlighted STAT family and AP-1-related signals, while functional enrichment implicated chromatin remodeling, DNA repair, and immune pathways, consistent with hallmarks of aging. These results suggest that age and sex shape the molecular architecture of sepsis, emphasizing the need for demography-aware approaches to understand its biology and prioritize pathways and regulators for validation towards precision diagnostics and therapeutics.