The Roles of Histone H3K18 Lactylation, Acetylation, and Lactylation/Acetylation Ratio as Potential Biomarkers in the Diagnosis and Severity Assessment of Sepsis and Septic Shock.

Introduction: The complex pathophysiology and diverse clinical manifestations of sepsis and septic shock continue to make early diagnosis and severity assessment challenging. Previous studies revealed the distinct roles of histone H3 lysine 18 lactylation (H3K18la) and H3 lysine 18 acetylation (H3K18ac) in infection. However, the functions and interactions of these modifications remain unclear. This study aimed to investigate the expression and roles of H3K18la and H3K18ac in patients with sepsis and septic shock.

Methods: This ambispective cohort study enrolled 86 critically ill patients (13 sepsis, 37 septic shock, and 36 noninfectious) and 12 healthy volunteers. Baseline information and laboratory data were collected. H3K18la and H3K18ac levels in peripheral blood mononuclear cells were detected via Western blotting. Serum cytokines, arginase-1 (ARG1), and Krüppel-like factor 4 (KLF4) mRNA were assayed via microsphere immunofluorescence and quantitative real-time polymerase chain reaction. The potential value of H3K18la, H3K18ac, and their ratio (H3K18la/ac) in the diagnosis and severity assessment was analyzed using logistic regression, receiver operating characteristic curve, and correlation analysis.

Results: Compared with the noninfectious group, the infectious group presented increased H3K18la and H3K18la/ac and decreased H3K18ac levels, with H3K18la/ac as an independent diagnosis biomarker. Compared with the sepsis group, the septic shock group presented higher H3K18la and H3K18la/ac and lower H3K18ac levels. H3K18la and H3K18la/ac levels correlated positively with sequential organ failure assessment (SOFA) scores, length of intensive care unit (ICU) stay, and mechanical ventilation time. H3K18ac levels correlated negatively with SOFA scores and mechanical ventilation time. H3K18la levels correlated negatively with interferon-α (IFN-α) and interleukin‑5 (IL‑5) and positively with IL-10 expression. H3K18ac levels correlated negatively with IL-6, IL-1β, IL-8, and IL-10 expression. H3K18la/ac levels correlated negatively with IFN-α and IL-5 and positively with IL-6, IL-8, and IL-10 expression. H3K18la and H3K18la/ac correlated positively, whereas H3K18ac correlated negatively with ARG1 and KLF4 mRNA expression.

Conclusions: H3K18la, H3K18ac, and H3K18la/ac can serve as biomarkers for the diagnosis and severity assessment of sepsis and septic shock through their involvement in inflammatory responses and macrophage polarization, thereby informing targeted therapies to modulate immune responses and improve patient outcomes.