Daily Sepsis Research Analysis

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are pathologically characterized by disruption of the alveolar-capillary barrier, excessive inflammatory responses, and dysregulated intra-pulmonary coagulation. Although inflammatory and thrombotic cascades have been extensively studied, endogenous epithelial-derived signaling mechanisms coordinating barrier stabilization with immunothrombotic restraint remain undefined. Here, we identify fibroblast growth factor 20 (FGF20) as a constitutive epithelial regulator suppressed in alveolar barrier-associated cells during sepsis-induced ALI. In a CLP rat model, both prophylactic and therapeutic administration of recombinant human FGF20 (rhFGF20) improved 7-day survival, attenuated pulmonary edema and inflammation, restored gas exchange, and preserved alveolar-capillary integrity. rhFGF20 restrained procoagulant and antifibrinolytic mediators tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) while suppressing NF-κB activation. Mechanistically, FGF20 acted through fibroblast growth factor receptor 1 (FGFR1) to engage the FGFR1-PI3K-AKT cascade. AKT activation bifurcated into two axes: (i) inhibition of NF-κB phosphorylation and nuclear translocation, restraining TF/PAI-1 transcription; and (ii) inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β) at Ser9, stabilizing epithelial and endothelial junctional proteins (E-cadherin, VE-cadherin, ZO-1). Pharmacological inhibition of FGFR1 or AKT abolished both barrier-protective and anticoagulant effects, confirming pathway dependency. Clinically, serum and bronchoalveolar lavage fluid FGF20 levels were reduced in ARDS patients and positively correlated with PaO₂/FiO₂ ratios, linking reduced FGF20 to disease severity. Collectively, these findings position FGF20 as an upstream integrator of structural and immunothrombotic homeostasis within the alveolar-capillary unit. Restoration of the FGF20-FGFR1 axis reconstitutes a proximal checkpoint stabilizing barrier architecture and constraining NF-κB-dependent procoagulant activation, highlighting FGF20 as a mechanistically grounded therapeutic target in sepsis-induced ALI/ARDS. CLINICAL SIGNIFICANCE.

BACKGROUND AND PURPOSE: Interferon-induced protein 27 (IFI27) is implicated in immune regulation, and regulatory T cells (Tregs) play a critical role in maintaining pulmonary immune homeostasis during sepsis. However, the relationship between IFI27 and Treg-mediated regulation in sepsis-associated lung injury remains unclear. This study aimed to investigate the role of IFI27 in modulating Treg function during sepsis. METHODS: Plasma IFI27 levels were measured in patients with sepsis and healthy controls. mRNA sequencing was performed to assess IFI27 expression profiles. RESULTS: Clinical analyses demonstrated that plasma IFI27 levels were positively correlated with sepsis severity. IFI27 expression was significantly increased in septic mice. Elevated IFI27 inhibited STAT5 phosphorylation, leading to a reduction in Treg abundance and IL-10 secretion, thereby exacerbating ferroptosis in pulmonary epithelial cells. Furthermore, IFI27 elevation in Tregs increased lipid peroxidation levels by suppressing the IL-10/STAT3 signaling pathway. CONCLUSIONS: These findings indicate that IFI27 is closely associated with sepsis severity and may serve as a potential prognostic indicator. Mechanistically, IFI27 suppresses Treg function and enhances ferroptosis in lung epithelial cells through inhibition of the IL-10/STAT3 signaling pathway, thereby aggravating sepsis-induced lung injury.

BACKGROUND: Sepsis is a life-threatening syndrome with dysregulated immune responses and multiple organ dysfunction. However, precise diagnostic biomarkers and effective therapeutic targets for this syndrome are still lacking. Protein ubiquitination modulates inflammatory regulation and immune cell function, but the specific immune cell subsets that drive ubiquitination-associated immune dysregulation in human sepsis have not been clearly identified. METHODS: An integrated analysis was performed using 315,220 single cells from two single-cell RNA sequencing (scRNA-seq) datasets in conjunction with independent bulk transcriptomic cohorts. We quantified cell-type responsiveness using Augur, inferred intercellular communication via CellChat, and identified ubiquitination-related gene networks through weighted gene co-expression network analysis (WGCNA) and subsequent multi-algorithm feature selection. Functional validation was conducted with lipopolysaccharide (LPS)-stimulated murine dendritic cells (DCs) line - DC2.4 RESULTS: conventional Dendritic cells (cDCs) were identified as the most transcriptionally perturbed immune population in sepsis, with subsequent subclustering revealing that the type-1 conventional dendritic cells (cDC1) subset specifically exhibited pronounced activation of ubiquitination signatures. Cell-cell communication analysis identified TNF signaling as a sepsis-specific pathway, in which cDC1 functions as a critical mediator predominantly via the TNF-TNFRSF1B axis. Four ubiquitination-related genes (CUL1, UBE2F, UBE2N and UBE3A) demonstrated reproducible diagnostic performance across three independent cohorts. Notably, UBE2F showed the strongest upregulation and functional relevance in sepsis models. Both CONCLUSIONS: Our results reveal cDC1 as a key immune cell subset involved in ubiquitination-mediated immune dysregulation in sepsis and suggests that UBE2F may serve as a potential diagnostic biomarker and therapeutic target.