Targeting mitochondrial complex I of CD177 neutrophils alleviates lung ischemia-reperfusion injury.

Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality following lung transplantation, with neutrophils playing a central role in its inflammatory pathology. Here, we employ single-cell RNA sequencing and spatial transcriptomics to investigate neutrophil subtypes in the lung ischemia-reperfusion injury (IRI) model. We identify CD177 neutrophils as an activated subpopulation that significantly contributes to lung injury and serves as an early biomarker for predicting severe PGD in human lung transplant recipients (area under the curve [AUC] = 0.871). CD177 neutrophils exhibit elevated oxidative phosphorylation and increased mitochondrial complex I activity, driving inflammation and the formation of neutrophil extracellular traps. Targeting mitochondrial function with the complex I inhibitor IACS-010759 reduces CD177 neutrophil activation and alleviates lung injury in both mouse IRI and rat left lung transplant models. These findings provide a comprehensive landscape of CD177 neutrophil-driven inflammation in lung IRI and highlight its potential value for future early diagnosis and therapeutic interventions.