Epigenetic regulation of neutrophil dysfunction in sepsis: mechanisms, biomarkers, and translational challenges

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection and remains a major challenge in critical care medicine. Neutrophils are central components of innate immunity, but their functions are markedly altered during sepsis. These alterations include disturbed granulopoiesis, prolonged survival, impaired migration, dysregulated inflammatory responses, imbalanced reactive oxygen species (ROS) production, and excessive formation of neutrophil extracellular traps (NETs). Epigenetic regulation may help explain how neutrophils acquire distinct functional states during infection and inflammation. However, current evidence comes from diverse clinical and experimental settings, and the contribution of epigenetic changes to neutrophil dysfunction in sepsis should be interpreted in relation to disease stage, tissue context, and model system. This review summarizes current evidence on the epigenetic regulation of neutrophil dysfunction in sepsis, with emphasis on DNA methylation, histone modifications, non-coding RNAs, and RNA modifications. We first outline key features of septic neutrophils, including abnormal development and lifespan, inflammatory dysregulation, impaired chemotaxis, ROS imbalance, and NETs formation. We then discuss how epigenetic mechanisms are involved in these processes by influencing chromatin accessibility, transcriptional activity, inflammatory responsiveness, and neutrophil fate. Particular attention is given to the context-dependent effects of epigenetic regulation. In some settings, these changes may support antimicrobial defense, whereas in others they may contribute to endothelial injury, immunothrombosis, tissue damage, and organ dysfunction. We also consider the differences between evidence from human sepsis studies, animal models, isolated-cell experiments, and non-sepsis inflammatory conditions. Finally, we discuss the possible translational implications of these findings for biomarker development and therapeutic exploration, with attention to validation, patient selection, timing of intervention, and the balance between limiting inflammatory injury and preserving antimicrobial defense. Epigenetic regulation provides a useful perspective for understanding the plasticity and dysfunction of neutrophils in sepsis. Future studies combining longitudinal clinical cohorts, single-cell and spatial multi-omics, and functional validation are needed to clarify which epigenetic changes are clinically relevant and whether they can be translated into reliable biomarkers or targeted therapeutic strategies.