HISTONE LACTYLATION IN IMMUNE CELLS AND ITS PREDICTIVE ROLE IN SEPSIS PROGRESSION: A PROSPECTIVE OBSERVATIONAL STUDY.

Background: Sepsis, a life-threatening condition caused by infection, induces dysregulated immune responses. Lactylation is a lactate-derived post-translational modification with roles in various cellular processes. We investigated lactylation levels in the immune cells of patients with sepsis and evaluated their association with disease progression.

Methods: In this prospective cohort study, blood samples were collected on days 1 and 3 from 58 intensive care unit patients, including critically ill controls and sepsis patients (survivors and non-survivors). Biochemical and clinical data were analyzed, and immune cells were isolated to measure pan-lysine lactylation (Pan Kla), H4K5la, and H3K56la levels using flow cytometry.

Results: Patients with sepsis exhibited significantly elevated neutrophil H4K5la levels compared with critically ill controls on day 1 (231.6 [174.9 - 361.9] vs. 127.5 [69.4 - 168.9] mean fluorescence intensity [MFI], P < 0.0001); similar trends were observed in monocytes, B cells, and T cells. Multivariate analysis identified neutrophil H4K5la levels as an independent predictor of sepsis. The combination of day 1 neutrophil H4K5la and C-reactive protein (CRP) levels improved diagnostic performance (area under the receiver operating characteristic curve = 0.902 [95% confidence interval, 0.795 - 0.964]). On day 3, non-survivors showed lower lactylation levels than survivors (monocyte Pan Kla: 79.8 [54.9 - 106.1] vs. 133.2 [112.3 - 259.2] MFI, P = 0.0334; T-cell H3K56la: 15.5 [8.2 - 28.1] vs. 37.2 [23.9 - 71.4] MFI, P = 0.0143).

Conclusions: Immune cell lactylation may serve as a biomarker for sepsis progression. The combination of neutrophil H4K5la and CRP enhances early diagnostic accuracy; reduced lactylation on day 3 may indicate poor prognosis.