To investigate the regulatory effect of glycyrrhizin (GL) on the release of neutrophil extracellular traps (NETs) from neutrophils in sepsis. HL-60 cells were induced to differentiate into neutrophil-like dHL-60 cells to establish a neutrophil-like sepsis model. Expression levels of high-mobility group box 1 (HMGB1), citrullinated histone H3 (Cit-H3), and Toll-like receptor 9 (TLR9) were assessed by Western blotting. Free DNA, a component of NETs, was quantified using a fluorescence microplate reader. Cellular immunofluorescence analysis was used to detect the expression of the key NETs protein, Cit-H3. dHL-60 cells stimulated with 200 ng/ml LPS exhibited the highest expression of Cit-H3. The neutrophil-like sepsis model showed significantly increased levels of Cit-H3 and HMGB1. GL intervention significantly reduced the expression levels of HMGB1 and Cit-H3 and decreased the free DNA level. These findings suggest that GL decreases HMGB1 expression and NET release in the neutrophil-like sepsis model. TLR9 expression was significantly elevated in the sepsis model. Exogenous recombinant human HMGB1 protein further increased TLR9 expression, while GL inhibited this increase. GL may inhibit NET release in sepsis through the HMGB1/TLR9 pathway.

Sepsis, a systemic inflammatory response to infection, remains a leading cause of mortality in intensive care units, with sepsis-induced immunosuppression being a critical pathophysiological process. In this study, we investigated the role of histone deacetylase 1 (HDAC1) in sepsis-induced CD8 ⁺ T cell exhaustion, a key driver of immunosuppression. Clinical analyses of patients with sepsis revealed that reduced peripheral blood lymphocyte levels, particularly CD8 ⁺ T cell depletion, strongly correlated with worsened outcomes. In a murine sepsis model, single-cell RNA-Seq revealed a significant decrease in the proportion of CD8 ⁺ T cells and an increase in the proportion of exhausted CD8 ⁺ T cells in mouse lungs. Adoptive transfer of CD8 ⁺ T cells effectively reduced sepsis mortality by preserving organ function. We further demonstrated that HDAC1 expression was significantly upregulated in CD8 ⁺ T cells from patients with sepsis. In vitro studies showed that HDAC1 inhibition preserved CD8 ⁺ T cell function by maintaining T cell activity and reducing the expression of inhibitory molecules such as PD-1. Pharmacological inhibition of HDAC1 reduced mortality and reversed CD8 ⁺ T cell exhaustion by restoring the balance between activator protein-1 (AP-1) and nuclear factor of activated T cells (NFAT). Additionally, we found that HDAC1 directly interacted with NFAT1, promoting its nuclear translocation and further enhancing the expression of inhibitory molecules. Our findings highlight HDAC1 as a potential therapeutic target for sepsis-induced immunosuppression. By elucidating the molecular mechanisms underlying HDAC1-mediated immunosuppression, we have provided potential strategies for developing immunomodulatory therapies for the treatment of sepsis.