Donor-Type-Dependent Heterogeneity of Ischemia–Reperfusion Injury in Lung Transplantation: A Multi-Cohort Transcriptomic Interaction Analysis of DCD Versus DBD Lungs

Background: Donation after circulatory death (DCD) and donation after brain death (DBD) donor lungs are widely used in lung transplantation yet managed as equivalent with respect to ischemia–reperfusion injury (IRI), despite fundamentally different ischemic backgrounds: warm ischemia in DCD versus neurogenic-inflammatory priming in DBD donors. Methods: Using GSE18995 (n = 35) as the core discovery interaction cohort for a 2 × 2 factorial limma model (donor type × reperfusion time), we integrated GSEA of metabolic and programmed cell death pathways, CIBERSORTx immune deconvolution, WGCNA, donor-stratified machine learning prediction of primary graft dysfunction (PGD), and CMap drug repurposing, validated externally in two independent cohorts (n = 153) and two PGD outcome sets (n = 55). Results: We identified 623 DCD-specific, 487 DBD-specific, and 1845 shared IRI genes. DCD grafts exhibited suppressed oxidative phosphorylation with compensatory glycolysis, dominant necroptosis and ferroptosis, and robust neutrophil influx, whereas DBD lungs showed mild metabolic disturbance, predominant pyroptosis and apoptosis, and M1 macrophage infiltration. Stratified PGD models (DCD AUC = 0.85; DBD AUC = 0.83) outperformed a universal model (AUC = 0.76). Conclusions: Molecularly distinct IRI signatures support donor-type-aware ex vivo lung perfusion protocols for precision lung transplantation.