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

Acta Pharmacologica Sinica (2026)Cite this article

Abstract

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).

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Fig. 1: Lrg1 deletion protects against CLP-induced pulmonary vascular barrier injury.
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Fig. 2: Endothelial LRG1 elevation is associated with increased vascular permeability in CLP-induced ALI.
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Fig. 3: LRG1-induced endothelial barrier dysfunction is mediated by proteasome-dependent degradation of VE-cadherin.
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Fig. 4: VE-cadherin degradation triggered by LRG1 requires the involvement of the E3 ubiquitin ligase MARCH2.
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Fig. 5: MARCH2 mediates K48-linked polyubiquitination and subsequent degradation of VE-cadherin.
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Fig. 6: LRG1, but not MARCH2 upregulation, is required for MARCH2-dependent VE-cadherin degradation.
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Fig. 7: Pharmacological inhibition of LRG1 prevents VE-cadherin degradation and reduces vascular leakage.
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Acknowledgements

This study was supported by grants from the Hubei Provincial Key Research and Development Program of China (2023BCB091, 2025BCB004), the National Science and Technology Maior Project (20232D0506504), and the National Natural Science Foundation of China (82372176, 82272217, and 82002026).

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Author notes

  1. These authors contributed equally: Xiao-wei Fang, Jia-ji Fu

Authors and Affiliations

  1. Department of Critical Care Medicine, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, 230001, China

    Xiao-wei Fang, Yi-ren Zhang, Yue Zhao & You Shang

  2. Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Jia-ji Fu, Ding-yu Zhang, Ji-qian Xu & You Shang

  3. State Key Laboratory of Virology, Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China

    Yang Qiu & Xi Zhou

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Contributions

XWF performed majority of the experiments. XWF and JJF conducted the in vitro experiment and helped with cell culture. YRZ and YZ performed the morphology analysis. XWF and JQX drafted the manuscript. YQ, XZ and DYZ provided technical advice. JQX and YS were responsible for concept, data collection and supervision, and reviewed and revised the draft. All authors read and approved the final manuscript.

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Correspondence to Ji-qian Xu or You Shang.

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Fang, Xw., Fu, Jj., Zhang, Yr. et al. Intracellular LRG1 recruits MARCH2 to ubiquitinate and degrade endothelial VE-cadherin in septic lung injury. Acta Pharmacol Sin (2026). https://doi.org/10.1038/s41401-026-01804-x

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