Intracellular LRG1 recruits MARCH2 to ubiquitinate and degrade endothelial VE-cadherin in septic lung injury.

Summary

Endothelial intracellular LRG1 drives septic ALI by recruiting MARCH2 to K48-polyubiquitinate VE-cadherin at K633, triggering proteasomal degradation and barrier failure. Genetic Lrg1 deletion and a PROTAC-based intervention preserved VE-cadherin and reduced hyperpermeability and lung injury in septic mice, defining a tractable endothelial target.

Key Findings

• Endothelial intracellular LRG1 is upregulated in septic ALI and promotes VE-cadherin degradation.
• LRG1 recruits MARCH2 to catalyze K48-linked polyubiquitination of VE-cadherin at K633, driving proteasomal degradation and barrier disruption.
• Genetic Lrg1 deletion or PROTAC-based pharmacologic intervention preserves VE-cadherin, reduces hyperpermeability, and mitigates ALI in septic mice.

Clinical Implications

Endothelial barrier–targeted strategies (e.g., LRG1/MARCH2 inhibition or VE-cadherin stabilization) could complement supportive care in sepsis-related ALI/ARDS and potentially reduce vascular leak and edema.

Limitations

• Preclinical findings; safety, delivery, and off-target effects of PROTACs not assessed in humans
• Generalizability beyond sepsis-induced ALI to other ARDS etiologies is uncertain

Future Directions

Validate LRG1/MARCH2–VE-cadherin signaling in human lung endothelium, optimize LRG1/MARCH2 inhibitors or VE-cadherin stabilizers, and test barrier-protective strategies in large-animal sepsis/ARDS models.