Cipepofol attenuates endothelial barrier dysfunction in acute lung injury through DUSP1-dependent suppression of MAPK signaling

Vascular endothelial cell dysfunction leads to the breakdown of endothelial barrier integrity, which contributes to sepsis-induced acute lung injury (ALI). The study investigates the role of Cipepofol in regulating endothelial permeability and inflammation during sepsis using a cecal ligation and puncture (CLP) mouse model and human umbilical vein endothelial cells (HUVECs). Our findings demonstrate that Cipepofol treatment inhibits cytoskeletal stress fiber formation and upregulates junction proteins VE-cadherin, thereby preserving endothelial barrier function. These effects were mediated through the γ-aminobutyric acid type A (GABA_A) receptor α1 subunit (GABA_A receptor α1). Cipepofol improved sepsis outcomes, including decreased lung injury, leukocyte infiltration, and vascular permeability. Mechanistically, cipepofol-dependent GABA_A receptor α1 modulated the expression of dual-specificity Phosphatase 1 (DUSP1) in lung tissue and endothelial cells of septic mice. DUSP1 knockdown exacerbated p38 and extracellular signal-regulated kinase (ERK)-MAPK signaling and mitochondrial dysfunction, and abolished the protective effects of Cipepofol against lipopolysaccharide (LPS)-induced mitochondrial oxidative stress. Conversely, genetic or pharmacological inhibition of GABA_A receptor α1 reversed Cipepofol-mediated suppression of p38/ERK-MAPK signaling and Reactive Oxygen Species (ROS) accumulation, confirming DUSP1 as a key downstream mediator. Together, our study unveils that Cipepofol preserves endothelial integrity by depending on GABA_A receptor α1 to modulate DUSP1 expression, thereby suppressing p38/ERK-MAPK signaling and mitochondrial dysfunction. These findings highlight a potential therapeutic strategy for sepsis-induced ALI.