Deubiquitinase USP2 accelerates endothelial glycocalyx degradation in sepsis-induced ALI by stabilizing MTCH2

Sepsis remains a major cause of death worldwide. The lung is particularly vulnerable, and sepsis‑induced acute lung injury (ALI) carries high mortality. Endothelial glycocalyx degradation is an early event that promotes vascular leakage and inflammation, but the upstream regulators of this process are poorly understood. Here we identify ubiquitin‑specific protease 2 (USP2) as a critical driver of pulmonary endothelial glycocalyx breakdown in sepsis. USP2 expression was markedly upregulated in lung endothelial cells of septic mice and in LPS-stimulated human endothelial cells. Endothelial‑specific Usp2 knockdown protected against cecal ligation and puncture (CLP)‑induced lung injury, vascular leakage, and glycocalyx degradation. Mechanistically, USP2 directly bound to mitochondrial carrier homolog 2 (MTCH2), an outer mitochondrial membrane protein, and removed K27‑linked ubiquitin chains at lysine 158, thereby stabilizing MTCH2. MTCH2 was required for USP2‑mediated downregulation of syndecan‑1 (SDC1), a core glycocalyx component, and its silencing rescued SDC1 levels in USP2‑overexpressing cells. Endothelial‑specific Mtch2 knockout mice phenocopied the protective effects of USP2 deficiency, including improved survival, preserved glycocalyx structure, and reduced inflammation. These findings uncover a USP2‑MTCH2 axis that links deubiquitination to glycocalyx integrity in the pulmonary endothelium during sepsis. Targeting this interaction may offer a new therapeutic strategy for septic ALI.