Daily Sepsis Research Analysis

Neutrophil extracellular traps (NETs) are reticular structures released by neutrophils, and the process of their formation is called NETosis. NETs play a key role in the pathological process of sepsis. However, the specific regulatory mechanism has not been fully clarified. This study finds that the levels of NETs in peripheral blood are significantly elevated in clinical sepsis patients and cecal ligation and puncture (CLP) mouse models, and the expression of Acod1 is closely related to the generation of NETs. Acod1 knockout led to a further increase in NETs levels in CLP mice, aggravated the inflammatory response, worsened organ damage, and reduced the survival rate. Further studies indicate that E3 ubiquitin ligase UBR5 interacts with PAD4 (one of the core proteins for NETs generation). Acod1/itaconate (ITA) enhanced the enzymatic activity of UBR5 through alkylation modification, promoting the K48-linked polyubiquitination and degradation of PAD4, thereby inhibiting NETosis. In conclusion, this study combines transcriptomics, metabolomics, genetic engineering, and co-immunoprecipitation techniques to reveal the molecular mechanism of Acod1/ITA in regulating NETs, providing new potential targets and theoretical basis for the treatment of sepsis.

BACKGROUND: Sepsis remains a major clinical challenge characterized by dysregulated immune response, coagulation abnormalities, and multiorgan failure, leading to high morbidity and mortality. OBJECTIVES: This study investigated the therapeutic potential of abelacimab, a monoclonal antibody targeting the plasma zymogen factor (F)XI, in a new baboon model of Staphylococcus aureus sepsis. METHODS: Healthy Papio anubis baboons were randomly assigned to control or abelacimab treatment groups. Both groups (n = 6, each) were intravenously infused with a median lethal (LD RESULTS: All 6 abelacimab-treated baboons survived until the 7-day endpoint, while 3 out of 6 untreated controls succumbed to sepsis within 102 hours. Abelacimab significantly attenuated sepsis-induced coagulopathy without signs of bleeding, as evidenced by biochemical tests and pathology analysis. Treated animals exhibited decreased proinflammatory cytokines, diminished neutrophil activation, and preservation of endothelial integrity, collectively conferring robust protection against organ damage. Proteomic analysis revealed that abelacimab modulated pathways related to coagulation, inflammation, and tissue injury, contributing to improved survival outcomes. CONCLUSION: FXI inhibition by abelacimab offers significant protection by attenuating activation of coagulation, reducing inflammation, and preventing organ failure. Targeting FXI may be a promising therapeutic strategy for managing sepsis by addressing multiple facets of its complex pathophysiology.

Sepsis-induced myocardial dysfunction (SIMD) remains a major contributor to sepsis-related mortality, driven by overwhelming inflammation, oxidative damage and impaired mitochondrial quality control. Narciclasine (Narc), a plant-derived diterpenoid, has demonstrated antioxidant and anti-inflammatory properties in various disease models. Here, we investigated whether Narc attenuates SIMD by inhibiting ferroptosis and promoting mitophagy. In both lipopolysaccharide (LPS) and cecal ligation and puncture (CLP) mouse models, prophylactic administration of Narc markedly improved 72-h survival and restored left ventricular ejection fraction (LVEF), fractional shortening (FS) and cardiac output in a dose-dependent manner. Biochemical assays revealed that SIMD hearts displayed iron overload, lipid peroxidation (elevated malondialdehyde) and glutathione depletion-hallmarks of ferroptosis-while Narc treatment replenished glutathione, reduced malondialdehyde levels, downregulated transferrin receptor (TFRC) and upregulated GPX4 and HO-1 expression. In neonatal rat cardiomyocytes challenged with LPS or the ferroptosis inducer erastin, Narc dose-dependently preserved cell viability, inhibited lipid peroxidation (BODIPY-C11 staining) and maintained intracellular glutathione. Concurrently, Narc ameliorated mitochondrial dysfunction: Seahorse analysis showed enhanced basal and maximal respiration, JC-1 staining demonstrated stabilized membrane potential, and immunofluorescence confirmed increased PINK1/PARK2 recruitment and LC3-ATP5B colocalization, indicating BNIP3-dependent mitophagy. Network pharmacology and molecular docking identified BNIP3 as a central target; siRNA-mediated BNIP3 knockdown abolished Narc's anti-ferroptotic and pro-mitophagic effects in vitro, and AAV9-driven BNIP3 silencing negated its survival and functional benefits in vivo. Together, these data establish that Narc mitigates SIMD by suppressing ferroptosis and preserving mitochondrial integrity through BNIP3-mediated mitophagy. This dual mechanism highlights Narc as a promising candidate for therapeutic intervention in sepsis-related cardiac injury.