Daily Sepsis Research Analysis

Sepsis-induced myocardial dysfunction (SIMD), a severe sepsis complication, is characterized by immune dysregulation, with neutrophils playing a central role. While the immunity-related GTPase family M protein (IRGM) in humans and its murine ortholog Irgm1 are key immune regulators, the precise contribution of neutrophil Irgm1 to SIMD pathogenesis remains unclear. This study aims to explore the involvement of neutrophil Irgm1 in SIMD and uncover its mechanisms. This research found that IRGM expression was upregulated in peripheral blood neutrophils from patients with SIMD and inversely correlated with disease severity. In mice, neutrophil-specific Irgm1 deficiency worsened CLP-induced cardiac dysfunction and myocardial inflammation. Mechanistically, Irgm1 interacted with the E3 ubiquitin ligase RING finger protein 213 (RNF213) to facilitate 15-lipoxygenase (Alox15) ubiquitination and degradation, thereby inhibiting neutrophil ferroptosis and suppressing the production of 15-HETE, which alleviates SIMD. In patients with SIMD, the expression levels of Alox15 and the concentrations of 15-HETE were positively correlated with disease severity. Notably, intraperitoneal administration of Alox15-targeting drug PD146176 significantly improved cardiac function in SIMD mice. Collectively, this study highlights the pivotal role of the Irgm1 in attenuating SIMD by restraining neutrophil ferroptosis and 15-HETE production. Irgm1 may serve as a promising prognostic biomarker and a valuable therapeutic target for SIMD.

Sepsis is a life-threatening syndrome driven by dysregulated thromboinflammation. Effective therapies are currently lacking due to the clinical limitations and bleeding risks associated with conventional anticoagulants. In this study, we demonstrate that Oroxylin A, a natural flavonoid, mitigates sepsis-associated coagulopathy by targeting arachidonate 12-lipoxygenase (ALOX12)-mediated lipid peroxidation. Using murine models of cecal ligation and puncture (CLP) and bacterial sepsis, we found that Oroxylin A significantly improved survival, restored platelet counts, and normalized coagulation parameters, including PT, APTT, and D-dimer levels. Furthermore, Oroxylin A reduced fibrin deposition and plasma tissue factor (F3) levels. Mechanistically, Oroxylin A promoted the ubiquitin-proteasome-dependent degradation of ALOX12, thereby suppressing lipid peroxidation markers (4-HNE and MDA) and the downstream interferon-beta (IFN-β)-driven transcription of F3. Additionally, Oroxylin A inhibited gasdermin D (GSDMD)-dependent pyroptosis, a key pathway for F3 release. Genetic ablation of ALOX12 abolished the therapeutic effects of Oroxylin A, confirming its target specificity. Molecular docking revealed that Oroxylin A binds to Asp632 within the catalytic domain of ALOX12, destabilizing the enzyme. These findings establish ALOX12 as a critical mediator of sepsis-associated coagulation and highlight the dual role of Oroxylin A in blocking pathological F3 expression and pyroptosis. This study provides a novel strategy for sepsis management by targeting lipid peroxidation upstream of thromboinflammatory cascades, offering improved safety over traditional anticoagulants.

Sepsis-induced hepatic dysfunction contributes significantly to poor clinical outcomes. Although the Fibrosis-4 (FIB-4) index is established for assessing chronic liver fibrosis, its utility as a prognostic marker for acute sepsis mortality-particularly in patients without pre-existing liver disease-remains unclear. We aimed to evaluate the predictive value of FIB-4 in sepsis using two large, multi-center databases.We conducted a multicenter retrospective study using two large critical care databases: MIMIC-IV (n = 13,983) and eICU (n = 9,976). Sepsis was defined based on established clinical criteria. Missing values were handled using multiple imputation to preserve data integrity. The optimal FIB-4 cutoff points were determined via outcome-based stratification (1.25). Patients were categorized into high and low FIB-4 groups accordingly. We applied restricted cubic spline (RCS) modeling to evaluate nonlinear trends, followed by weighted Cox regression to determine independent associations with in-hospital mortality. Kaplan-Meier survival curves assessed time-to-event differences, while subgroup analyses, ROC curves, and sensitivity analyses explored effect consistency and underlying biological pathways. Across 23,959 sepsis patients from the MIMIC-IV and eICU databases, elevated FIB-4 levels were significantly associated with in-hospital mortality (P < 0.001). An FIB-4 index > 1.25 served as an independent risk factor for mortality (adjusted HRs: 1.38-1.55) and outperformed traditional SOFA and APACHE scores in prognostic discrimination. Kaplan-Meier curves showed significantly reduced survival in the high FIB-4 group. Importantly, sensitivity analyses excluding patients with known liver disease, suspected MASLD, or cardiac admissions confirmed the robustness of these findings. The FIB-4 index serves as a robust, independent prognostic marker for in-hospital mortality in sepsis patients, outperforming traditional scores such as SOFA and APACHE II in predictive accuracy. Crucially, its prognostic value persists even after excluding patients with pre-existing liver disease or acute cardiogenic hepatic congestion, suggesting it reflects broader sepsis-induced physiological derangements rather than solely baseline hepatic fibrosis. Given its simplicity and reliance on routinely available laboratory parameters, FIB-4 offers a practical, accessible tool for early risk stratification in the intensive care setting.