Weekly Sepsis Research Analysis
This week’s sepsis literature highlights mechanistic breakthroughs and actionable diagnostic/therapeutic leads. Top reports identify a neutrophil–endothelium DLL4–Notch1 axis driving endothelial PANoptosis in septic lung injury, reveal heme as a STING ligand that promotes cardiac endothelial senescence, and connect IFNβ–MALAT1–caspase‑11 signaling to early DIC risk. Collectively these studies provide high-priority molecular targets and bedside-predictive biomarkers that could be translated into
Summary
This week’s sepsis literature highlights mechanistic breakthroughs and actionable diagnostic/therapeutic leads. Top reports identify a neutrophil–endothelium DLL4–Notch1 axis driving endothelial PANoptosis in septic lung injury, reveal heme as a STING ligand that promotes cardiac endothelial senescence, and connect IFNβ–MALAT1–caspase‑11 signaling to early DIC risk. Collectively these studies provide high-priority molecular targets and bedside-predictive biomarkers that could be translated into early-risk stratification and targeted interventions.
Selected Articles
1. DLL4+ neutrophils promote Notch1-mediated endothelial PANoptosis to exacerbate acute lung injury in sepsis.
This preclinical study shows that eCIRP-induced DLL4+ neutrophils bind endothelial Notch1 and trigger ZBP1-initiated PANoptosis in pulmonary endothelium, worsening sepsis-associated acute lung injury. A rationally designed Notch1–DLL4 inhibitory peptide (NDI) reduced endothelial PANoptosis, vascular leak, lung injury markers, and improved survival in sepsis models.
Impact: Identifies a specific neutrophil–endothelial ligand–receptor interaction driving a novel form of inflammatory cell death (PANoptosis) and delivers a targeted peptide inhibitor with in vivo efficacy, creating a direct translational path for sepsis lung injury therapy.
Clinical Implications: If safety and pharmacology are established, Notch1–DLL4 blockade could be tested in early-phase trials to prevent endothelial PANoptosis, reduce vascular leak, and improve outcomes in sepsis-induced acute lung injury.
Key Findings
- eCIRP induces DLL4+ neutrophils that increase in blood and lung during sepsis.
- DLL4 binds Notch1 on pulmonary endothelium to activate intracellular Notch1 and amplify ZBP1-mediated endothelial PANoptosis.
- A Notch1–DLL4 inhibitory peptide (NDI) reduced endothelial PANoptosis, lung permeability, inflammatory markers, and improved survival in sepsis models.
2. Heme drives cardiac endothelial senescence in sepsis via STING activation.
This murine mechanistic study demonstrates that heme accumulation in sepsis directly activates STING, promoting cardiac endothelial senescence and impairing cardiac recovery. Pharmacologic STING inhibition and enhanced heme clearance with hemopexin reduced endothelial senescence and improved cardiac outcomes, suggesting actionable interventions linking hemolysis to cardiac dysfunction.
Impact: Reveals a new pathogenic link between hemolysis and cardiac dysfunction via heme-induced STING activation and cellular senescence, identifying STING inhibition and heme-scavenging as plausible therapeutic strategies.
Clinical Implications: Supports evaluation of heme-scavenging (e.g., hemopexin) and STING inhibitors in translational studies to prevent or mitigate sepsis-associated cardiomyopathy; encourages measurement of heme/STING activity as potential biomarkers.
Key Findings
- Cardiac endothelial cells are the predominant senescent population in septic hearts.
- Heme acts as a novel ligand that promotes STING polymerization/activation, driving endothelial senescence.
- STING inhibition or heme clearance (hemopexin) reduced endothelial senescence and improved cardiac recovery in septic mice.
3. A Critical Role for MALAT1 in Gram-negative Bacteria-induced Coagulation via Regulation of Caspase-11 signaling.
This study integrates human biomarker data and mechanistic mouse experiments to show admission plasma IFNβ predicts 48-hour onset of septic DIC and that IFNβ induces macrophage MALAT1. MALAT1 suppresses GPX4 activity, promoting caspase‑11 activation and immunocoagulation; macrophage-specific Malat1 deletion protected against bacteria-induced coagulation in models.
Impact: Bridges predictive human biomarker (IFNβ) with a defined macrophage lncRNA mechanism (MALAT1→GPX4↓→caspase‑11↑) that underlies early sepsis-associated coagulopathy, offering both prognostic and therapeutic entry points.
Clinical Implications: Admission IFNβ merits prospective validation as an early DIC risk marker; MALAT1/caspase‑11/GPX4 axis represents a candidate for targeted interventions aimed at preventing sepsis-associated coagulopathy.
Key Findings
- Plasma IFNβ at admission correlated with 48-hour onset of septic DIC in patients.
- IFNβ stimulates macrophage MALAT1 expression in response to gram-negative bacteria.
- Macrophage-specific Malat1 deletion restored GPX4 activity, reduced caspase‑11 activation and protected against bacteria-induced coagulation.