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

Summary

This mechanistic study reveals that endothelial intracellular LRG1 drives VE-cadherin K48-linked polyubiquitination via MARCH2, promoting proteasomal degradation and barrier failure in septic ALI. Genetic Lrg1 deletion and a PROTAC-based approach preserved VE-cadherin, reduced hyperpermeability, and mitigated lung injury in septic mice, highlighting LRG1/MARCH2 as a therapeutic axis.

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 lysine 633.
• Genetic Lrg1 deletion or PROTAC-based intervention preserves VE-cadherin, reduces hyperpermeability, and mitigates lung injury in septic mice.

Clinical Implications

Targeting LRG1 or its interaction with MARCH2 could preserve VE-cadherin and reduce vascular leakage in sepsis-induced ALI/ARDS, motivating translational development of inhibitors or degraders.

Limitations

• Preclinical models; human validation of the LRG1–MARCH2–VE-cadherin axis remains to be established.
• Potential off-target effects and pharmacokinetics of PROTACs in sepsis are not addressed.

Future Directions

Validate LRG1/MARCH2 pathway activity and biomarkers in human sepsis cohorts; optimize LRG1 inhibitors/PROTACs and assess efficacy and safety in large-animal models toward early-phase trials.