A Critical Role for MALAT1 in Gram-negative Bacteria-induced Coagulation via Regulation of Caspase-11 signaling.
Summary
Plasma IFNβ at admission predicts 48-hour DIC onset in sepsis, and mechanistic experiments show IFNβ induces macrophage MALAT1, which suppresses GPX4 and promotes caspase-11–dependent immunocoagulation. Macrophage-specific Malat1 deletion restores GPX4 activity, reduces LPS internalization and caspase-11 activation, and protects against coagulation.
Key Findings
- Admission plasma IFNβ correlates with 48-hour onset of septic DIC, whereas HMGB1 does not.
- IFNβ induces macrophage MALAT1, which suppresses GPX4 via YY1/Hba-a1, enhancing LPS internalization and caspase-11 activation.
- Macrophage Malat1 deletion limits caspase-11/GSDMD-dependent PS exposure and protects against bacteria-induced coagulation.
Clinical Implications
IFNβ measurement may aid early DIC risk stratification in sepsis, and therapeutically targeting MALAT1 or restoring GPX4 activity could mitigate immunothrombosis.
Why It Matters
Bridges clinical prediction (IFNβ) with a novel MALAT1–caspase-11 mechanism of sepsis-associated DIC, nominating actionable biomarkers and targets.
Limitations
- Clinical cohort size and external validation are not specified; predictive thresholds were not provided.
- Translational therapeutics (e.g., MALAT1 targeting) remain untested in humans.
Future Directions
Define IFNβ thresholds for DIC prediction in multi-center cohorts; develop MALAT1/GPX4-modulating therapies and assess safety/efficacy in preclinical large animals.
Study Information
- Study Type
- Cohort
- Research Domain
- Prognosis
- Evidence Level
- II - Prospective biomarker assessment in sepsis with supportive mechanistic animal studies.
- Study Design
- OTHER