The Epigenetics of Sepsis: How Gene Modulation Shapes Outcomes

Abstract

Sepsis is a complex and heterogeneous condition, arising from a disrupted immune response to infection that can progress to organ failure and carries a high risk of death. In recent years, growing attention has been paid to the role of epigenetic mechanisms-including DNA methylation, histone modifications, non-coding RNAs, and RNA methylation-in shaping immune activity during sepsis. These processes affect immune functions such as macrophage polarization, cytokine release, and the exhaustion of immune cells, and they help explain the shift from an initial phase of overwhelming inflammation to a later state of immune suppression. Epigenetic alterations also contribute to tissue-specific damage, notably in the lungs, kidneys, and heart, and have been linked to disease severity and clinical prognosis. Advances in transcriptomic and epigenetic profiling have made it possible to distinguish molecular subtypes of septic patients, each with distinct immune features and varied responses to treatments such as corticosteroids and metabolic therapies. Emerging biomarkers-like AQP5 methylation, histone lactylation (H3K18la), and m⁶A RNA methylation-are opening new options for patient classification and more tailored therapeutic strategies. This review examines the current understanding of how epigenetic regulation contributes to the pathophysiology of sepsis and considers its implications for developing more individualized approaches to care.

Keywords: DNA methylation; epigenetics; histone modifications; ncRNAs; sepsis.

Figure 1

Epigenetic Modifications in Sepsis-Induced Immunosuppression. Legend: LPS: lipopolysaccharide, DAMPs: damage-associated molecular patterns, PAMPS: pathogen-associated molecular patterns, miRNAs: microRNAs, lncRNAs: long non-coding RNAs, NEAT1: Nuclear Paraspeckle Assembly Transcript, m⁶A: N6-methyladenosine, METTL3: methyltransferase-like 3, FTO: fat mass and obesity-associated protein, YTHDF1: YTH N6-Methyladenosine RNA Binding Protein 1, NETs: neutrophil extracellular traps, AKI: acute kidney injury, ALI: acute lung injury, SICD: sepsis-induced cardiac dysfunction.

Figure 2

DNA methylation mechanisms involved in altered inflammatory response in sepsis. NO: nitric oxyde, -CH₃: methy group, AQP5: aquaporin-5, APC: antigen-presenting cell, IL: interleukin, TNF: tumor necrosis factor, SIRS: systemic inflammatory response syndrome, CARS: compensatory anti-inflammatory response syndrome.