USP7 promotes endothelial activation to aggravate sepsis-induced acute lung injury through PDK1/AKT/NF-κB signaling pathway.

Disruption of the endothelial cell barrier and the subsequent inflammatory response represent a central pathological feature of acute lung injury (ALI). Ubiquitination plays a pivotal role in regulating protein stability, intracellular transport, and enzyme activity, which is typically reversed by deubiquitinating enzymes. Nevertheless, the function of deubiquitinating enzymes in endothelial biology and in ALI remains largely uninvestigated. The present study demonstrates that the expression of USP7 is increased in instances of endothelial inflammation and ALI. The knockdown or inhibition of USP7 using specific inhibitors was observed to significantly reduce the TNF-α-induced inflammatory response of endothelial cells and their adhesion capacity to monocytes. Conversely, the overexpression of USP7 was observed to promote the inflammatory response and adhesion capacity of endothelial cells. The specific inhibitors of USP7 were found to be effective in mitigating acute lung injury induced by LPS. From a mechanistic perspective, our findings indicate that USP7 binds and deubiquitinates PDK1, thereby stabilizing PDK1 and promoting the activity of the inflammatory pathway in endothelial cells. In conclusion, our findings demonstrate the role of a novel USP7-PDK1 signaling axis in regulating TNF-α-induced vascular endothelial injury and reveal that USP7 is a deubiquitylating enzyme of PDK1. These observations suggest that targeting the USP7-PDK1 axis may offer a promising therapeutic strategy for the treatment of acute lung injury.