Multi-omics analysis identifies NFIL3 as a hypoxia-associated immune regulator in septic cardiomyopathy.

Background: Sepsis is a life-threatening syndrome caused by a dysregulated host response to infection and is associated with high mortality in intensive care units. Septic cardiomyopathy (SCM) is a frequent and severe complication of sepsis; however, its underlying molecular mechanisms and immune regulatory networks remain incompletely understood. Methods: Transcriptomic profiling of septic mouse myocardium was performed to characterize hypoxia-associated immune remodeling at both bulk and single-cell levels. Hypoxia-related genes were identified through integrative differential expression and network analyses. These candidate genes were mapped to human peripheral blood transcriptomic datasets for machine learning-based biomarker selection, followed by two-sample Mendelian randomization analysis to assess their causal relevance to sepsis. Results: Septic myocardium exhibited prominent activation of hypoxia-related signaling accompanied by immune landscape remodeling, characterized by increased macrophage infiltration. NFIL3, TGM2, and SDC4 were identified as key hypoxia-associated hub genes and showed robust diagnostic performance in independent human peripheral blood cohorts. Two-sample Mendelian randomization analysis demonstrated that genetically predicted higher NFIL3 expression was significantly associated with increased sepsis risk. Single-cell analysis revealed predominant enrichment of Conclusion: This study systematically delineates the molecular basis of septic cardiomyopathy, highlighting hypoxia-driven immune dysregulation as a central pathogenic mechanism. As a key hypoxia-responsive immune regulator, NFIL3 may play a critical role in the development of septic cardiac injury. These findings identify novel molecular targets for the early diagnosis and therapeutic intervention of sepsis and its associated myocardial damage.