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

Endothelial barrier dysfunction and consequent vascular injury are central contributors to acute lung injury (ALI) during sepsis. However, the underlying mechanisms remain incompletely understood, and effective therapeutic strategies targeting endothelial repair are still lacking. Here, we identify that intracellular leucine-rich α2-glycoprotein 1 (LRG1) in endothelial cells (EC) is significantly upregulated and directly promotes the degradation of vascular endothelial cadherin (VE-cadherin), a core adherens junction protein essential for maintaining vascular barrier integrity in septic ALI. Mechanistically, LRG1 recruits the E3 ubiquitin ligase membrane-associated ring-CH-type finger 2 (MARCH2) to catalyze K48-linked polyubiquitination of VE-cadherin at lysine 633, leading to its proteasomal degradation and subsequent endothelial barrier disruption. Genetic deletion of Lrg1 or pharmacological intervention with a proteolysis targeting chimera (PROTAC)-based degradation strategy significantly reduced VE-cadherin loss, alleviated endothelial hyperpermeability, and mitigated ALI in septic mice. Collectively, our study elucidates a previously unrecognized role of endothelial LRG1 in disrupting EC adherens junctions, providing novel insights into the pathogenesis of sepsis-associated injury and proposing a potential therapeutic strategy for sepsis-induced ALI and acute respiratory distress syndrome (ARDS).