Endothelial GSDMD underlies LPS-induced systemic vascular injury and lethality.

Summary

Using cell type–specific mouse models, the authors show that endothelial (but not myeloid) GSDMD mediates systemic vascular injury and lethality in endotoxemia and sepsis via a hepatocyte GSDMD–HMGB1–RAGE axis. Pharmacologic inhibition of endothelial GSDMD with a peptide attenuated endothelial damage and improved survival, positioning endothelial GSDMD as a promising therapeutic target.

Key Findings

• LPS upregulates endothelial GSDMD in aorta and lung microvessels.
• Endothelial, but not myeloid, Gsdmd deletion protects against vascular injury and death in mouse endotoxemia and sepsis models.
• Hepatocyte GSDMD drives HMGB1 release that activates endothelial RAGE, causing systemic vascular injury and acute lung injury.
• A polypeptide inhibitor of endothelial GSDMD reduces endothelial damage and improves survival in vivo.

Clinical Implications

While preclinical, the data support pursuing endothelial-targeted GSDMD inhibitors and HMGB1–RAGE pathway modulators as candidate therapies for septic shock and endotoxemia, and motivate biomarker development around endothelial pyroptosis.

Limitations

• Preclinical mouse models may not fully recapitulate human sepsis heterogeneity.
• Translational feasibility and safety of the peptide inhibitor remain untested in humans.

Future Directions

Develop endothelial-targeted GSDMD inhibitors with pharmacokinetic and safety profiles suitable for clinical testing; validate endothelial pyroptosis biomarkers in human sepsis and evaluate the HMGB1–RAGE axis as a therapeutic target.