Activation of PANoptosis and ferroptosis during ex vivo lung perfusion in human lungs

Background: A recent study demonstrated upregulation of PANoptosis-related genes during reperfusion in human lung transplants. However, the impact of ex vivo lung perfusion (EVLP) on different cell death pathways and their relationship with inflammatory genes and clinical characteristics remains unknown. Methods: We conducted transcriptomic analyses on pre- and post-EVLP biopsies from 49 donation after brain death (DBD) and 39 donation after circulatory death (DCD) lungs. Gene set enrichment analysis (GSEA) and single-sample GSEA were used to assess the enrichment of cell death and inflammatory pathways. We further explored the relationships between these pathways, donor characteristics, and clinical outcomes. Results: DBD lungs showed significant enrichment of apoptosis and ferroptosis gene sets compared to DCD lungs. During EVLP, pyroptosis, apoptosis, necroptosis, and ferroptosis gene sets were significantly upregulated and strongly correlated with inflammatory pathways in both DBD and DCD donor lungs. Donor age, sex, and smoking history were associated with specific cell death pathways. In DCD lungs, the expression of ferroptosis-related genes was associated with recipient early outcomes. Conclusion: The expression of cell death gene sets is donor-type specific. The identification of multiple cell death and inflammatory pathways during EVLP provides potential therapeutic targets to improve donor lung quality and enhance clinical outcomes.