Metabolomic atlas of ischemia-reperfusion injury in human lung transplants: Mitochondrial stress and primary graft dysfunction.

Ischemia-reperfusion injury drives primary graft dysfunction (PGD) in lung transplantation, yet the metabolic landscape of this process remains unclear. We performed longitudinal untargeted metabolomic studies on lung grafts collected before and after reperfusion, from 39 patients with PGD grade 3 (PGD3) and 40 patients without. The expression levels and pathways of identified metabolites were analyzed and correlated with donor/recipient conditions and early clinical outcomes. A total of 443 metabolites were detected, and metabolites that significantly changed following reperfusion were mapped to relevant biological pathways. Reperfusion significantly reduced lysophospholipids in the lung tissue. Metabolomic alterations in carbohydrates, fatty acids, and amino acids collectively indicate mitochondrial stress. PGD3 cases showed significantly lower antioxidant levels after cold ischemia time (CIT) and elevated taurine-conjugated bile acids upon reperfusion. Enrichment analysis revealed that in CIT samples, glutathione metabolism was associated with PGD, and the dipeptide pathway was associated with ventilation days. During reperfusion, bile acid metabolism demonstrated an inverse correlation with lung oxygenation function, and oxidative phosphorylation was associated with intensive care unit stay. This study establishes a metabolomic atlas in human lung transplant, linking primary graft dysfunction to mitochondrial stress. The mitochondrial and redox pathways emerged as potential therapeutic targets to protect lung grafts from reperfusion injury.