DYRK2 Modulates Neutrophil Extracellular Trap (NET) Release in Sepsis-Induced Acute Lung Injury: Mechanisms and Potential Therapeutic Targets

Sepsis-induced acute lung injury represents a life-threatening complication with mortality rates exceeding 40%. Neutrophil extracellular traps and hypoxia-induced glycolytic reprogramming are emerging as critical pathogenic mechanisms. Dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) regulates TANK-binding kinase 1 (TBK1), which promotes glycolysis through glucose transporter 1 (Glut1) translocation. This study investigated whether DYRK2 modulates neutrophil extracellular trap formation through glycolysis-related pathways in sepsis-induced acute lung injury. Three sepsis datasets (GSE26440, GSE65682, GSE95233) from the Gene Expression Omnibus database were analyzed using weighted gene co-expression network analysis and machine learning algorithms (LASSO regression, random forest, support vector machine-recursive feature elimination) to identify hypoxia-related biomarkers. A murine sepsis model was established via cecal ligation and puncture. Neutrophils were isolated from mouse bone marrow and stimulated with lipopolysaccharide (3 µg/mL) for 12 h. DYRK2 overexpression was achieved using lentiviral transduction. Neutrophil extracellular trap formation was assessed by Western blot for citrullinated histone H3, immunofluorescence, and Sytox Green staining. Protein interactions were examined using co-immunoprecipitation and proximity ligation assays. Inflammatory cytokines were quantified by enzyme-linked immunosorbent assay. Bioinformatics analysis identified DYRK2, CXXC5, and SMAD3 as key hypoxia-related genes in sepsis, with DYRK2 showing the strongest downregulation and negative correlation with neutrophil infiltration. In septic mice, lung tissue and blood exhibited significantly decreased DYRK2 expression alongside increased neutrophil extracellular trap markers and inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, interleukin-6; P < 0.01). DYRK2 overexpression in neutrophils suppressed both NET release and inflammatory cytokine secretion (P < 0.01). Mechanistically, DYRK2 interacted with TBK1, and TBK1 bound to Glut1. DYRK2 overexpression downregulated both TBK1 and Glut1 protein expression, effectively inhibiting glycolysis-driven neutrophil extracellular trap formation. DYRK2 protects against sepsis-induced acute lung injury by suppressing neutrophil extracellular trap release through negative regulation of the TBK1-Glut1 glycolytic signaling axis. These findings identify DYRK2 as a potential therapeutic target for mitigating neutrophil extracellular trap-mediated lung injury in septic patients.