{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T05:03:06Z","timestamp":1789707786915,"version":"4.0.1"},"reference-count":49,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>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\u2013reperfusion 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 \u00d7 2 factorial limma model (donor type \u00d7 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.<\/jats:p>","DOI":"10.3390\/genes17091127","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T10:09:17Z","timestamp":1789553357000},"page":"1127","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Donor-Type-Dependent Heterogeneity of Ischemia\u2013Reperfusion Injury in Lung Transplantation: A Multi-Cohort Transcriptomic Interaction Analysis of DCD Versus DBD Lungs"],"prefix":"10.3390","volume":"17","author":[{"given":"Zezhao","family":"Ji","sequence":"first","affiliation":[{"name":"Department of Pathology, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"given":"Yanbin","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Integrative Chinese and Western Medicine, Shanghai Pulmonary Hospital, Tongji University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4748-3225","authenticated-orcid":false,"given":"Lixin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Integrative Chinese and Western Medicine, Shanghai Pulmonary Hospital, Tongji University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e14884","DOI":"10.1111\/ctr.14884","article-title":"Lung transplantation from donation after circulatory death, evolution, and current status in the United States","volume":"37","author":"Furukawa","year":"2023","journal-title":"Clin. Transplant."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.ccm.2022.10.006","article-title":"Expanding the Lung Donor Pool: Donation After Circulatory Death, Ex-Vivo Lung Perfusion and Hepatitis C Donors","volume":"44","author":"Saddoughi","year":"2023","journal-title":"Clin. Chest Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e70442","DOI":"10.1111\/ctr.70442","article-title":"Changing Landscape of Procurement of Deceased Donor Organs: An Analysis of National Trends","volume":"40","author":"Bashian","year":"2026","journal-title":"Clin. Transplant."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"109827","DOI":"10.1016\/j.surg.2025.109827","article-title":"Lung transplantation following donation after circulatory death: Five-year US experience","volume":"190","author":"Maksimuk","year":"2026","journal-title":"Surgery"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1016\/j.healun.2024.12.010","article-title":"Short and long-term outcomes of lung transplantation from brain death vs. circulatory death donors: A meta-analysis of comparative studies","volume":"44","author":"Spadaccio","year":"2025","journal-title":"J. Heart Lung Transplant."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Berzenji, L., Hendriks, J.M.H., Verleden, S.E., Yogeswaran, S.K., Wen, W., Lauwers, P., Verleden, G., Paep, R.D., Mertens, P., and Rodrigus, I. (2025). Lung Ischemia\u2013Reperfusion Injury in Lung Transplant Surgery: Where Do We Stand?. Antioxidants, 14.","DOI":"10.3390\/antiox14111295"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6618","DOI":"10.21037\/jtd-2021-18","article-title":"Primary graft dysfunction: What we know","volume":"13","author":"Clausen","year":"2021","journal-title":"J. Thorac. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Van Slambrouck, J., Van Raemdonck, D., Vos, R., Vanluyten, C., Vanstapel, A., Prisciandaro, E., Willems, L., Orlitov\u00e1, M., Kaes, J., and Jin, X. (2022). A Focused Review on Primary Graft Dysfunction after Clinical Lung Transplantation: A Multilevel Syndrome. Cells, 11.","DOI":"10.3390\/cells11040745"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1016\/j.healun.2021.07.012","article-title":"International consensus recommendations for anesthetic and intensive care management of lung transplantation. An EACTAIC, SCA, ISHLT, ESOT, ESTS, and AST approved document","volume":"40","author":"Marczin","year":"2021","journal-title":"J. Heart Lung Transplant."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Sandiumenge, A., Bello, I., Coll-Torres, E., Gomez-Brey, A., Franco-Jarava, C., Mi\u00f1ambres, E., P\u00e9rez-Redondo, M., Mosteiro, F., S\u00e1nchez-Moreno, L., and Crowley, S. (2024). Systemic Inflammation Differences in Brain-vs. Circulatory-Dead Donors: Impact on Lung Transplant Recipients. Transpl. Int., 37.","DOI":"10.3389\/ti.2024.12512"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Premachandra, A., Pascale, F., Mimbimi, C., Jacqmin, S., Jouneau, L., Richard, C., Gelin, V., Bevilacqua, C., Lecardonnel, J., and Rivi\u00e8re, J. (2026). Resilience of lung grafts to warm ischemia: Assessment by ex vivo perfusion using functional and molecular analysis. Transpl. Int., 39.","DOI":"10.3389\/ti.2026.16314"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e1904","DOI":"10.1097\/TXD.0000000000001904","article-title":"A Whole-body Cooling Strategy in Uncontrolled Donation After Circulatory Death: Insights from a Porcine Ex Vivo Lung Perfusion Model","volume":"12","author":"Niikawa","year":"2026","journal-title":"Transplant. Direct"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Gori, F., Fumagalli, J., Lonati, C., Carlin, A., Leonardi, P., Biancolilli, O., Rossetti, A., Righi, I., Tosi, D., and Palleschi, A. (2022). Lung Biomolecular Profile and Function of Grafts from Donors after Cardiocirculatory Death with Prolonged Donor Warm Ischemia Time. J. Clin. Med., 11.","DOI":"10.3390\/jcm11113066"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Palleschi, A., Zanella, A., Citerio, G., Musso, V., Rosso, L., Tosi, D., Fumagalli, J., Bonitta, G., Benazzi, E., and Lopez, G. (2023). Lung Transplantation from Controlled and Uncontrolled Donation After Circulatory Death (DCD) Donors with Long Ischemic Times Managed by Simple Normothermic Ventilation and Ex-Vivo Lung Perfusion Assessment. Transpl. Int., 36.","DOI":"10.3389\/ti.2023.10690"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4234","DOI":"10.1097\/MS9.0000000000004986","article-title":"Evolution in lung IRI cell death research: A 20-year global bibliometric study (2005\u20132024)","volume":"88","author":"Yang","year":"2026","journal-title":"Ann. Med. Surg."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1186\/s12931-026-03794-0","article-title":"Necroptosis in alveolar epithelium orchestrates lung ischemia-reperfusion injury: A multi-omics study","volume":"27","author":"Liang","year":"2026","journal-title":"Respir. Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zhao, Y., Main, K., Aujla, T., Keshavjee, S., and Liu, M. (2023). Necroptosis in Organ Transplantation: Mechanisms and Potential Therapeutic Targets. Cells, 12.","DOI":"10.20944\/preprints202308.0558.v1"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Li, J., Ma, X., Huang, J., Yu, Y., Lou, Z., Liang, F., Hu, X., Fang, Q., Wang, Y., and Liu, M. (2026). GSK\u2019872 mitigates ischemia-reperfusion injury in rat lung transplants by regulating PANoptosis and inflammation in cell type specific manner. Cell Commun. Signal.","DOI":"10.1186\/s12964-026-03037-1"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1097\/TP.0000000000005268","article-title":"Ischemia\/Reperfusion Upregulates Genes Related to PANoptosis in Human Lung Transplants","volume":"109","author":"Zhao","year":"2025","journal-title":"Transplantation"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"uxaf046","DOI":"10.1093\/cei\/uxaf046","article-title":"Primary graft dysfunction after Lung transplantation: Unveiling the role of innate immunity","volume":"219","author":"Gao","year":"2025","journal-title":"Clin. Exp. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1016\/j.healun.2025.04.003","article-title":"Activation of PANoptosis and ferroptosis during ex vivo lung perfusion in human lungs","volume":"44","author":"Zhao","year":"2025","journal-title":"J. Heart Lung Transplant."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.healun.2024.09.028","article-title":"Loss of Nr4a1 ameliorates endothelial cell injury and vascular leakage in lung transplantation from circulatory-death donor","volume":"44","author":"Kawana","year":"2025","journal-title":"J. Heart Lung Transplant."},{"key":"ref_23","first-page":"3781","article-title":"Ex vivo lung perfusion with GLP-1R agonist mitigates ischemia\/reperfusion injury through pyroptosis modulation in lung transplantation\u2014An experimental study","volume":"111","author":"Zhang","year":"2025","journal-title":"Int. J. Surg."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Bonneau, S., Landry, C., B\u00e9gin, S., Adam, D., Villeneuve, L., Clavet-Lanthier, M., Dasilva, A., Charles, E., Dumont, B.L., and Neagoe, P.-E. (2022). Correlation between Neutrophil Extracellular Traps (NETs) Expression and Primary Graft Dysfunction Following Human Lung Transplantation. Cells, 11.","DOI":"10.3390\/cells11213420"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4173","DOI":"10.1038\/s41467-022-31811-5","article-title":"Reduction of primary graft dysfunction using cytokine adsorption during organ preservation and after lung transplantation","volume":"13","author":"Ghaidan","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/s41587-019-0114-2","article-title":"Determining cell type abundance and expression from bulk tissues with digital cytometry","volume":"37","author":"Newman","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/nmeth.3337","article-title":"Robust enumeration of cell subsets from tissue expression profiles","volume":"12","author":"Newman","year":"2015","journal-title":"Nat. Methods"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Langfelder, P., and Horvath, S. (2008). WGCNA: An R package for weighted correlation network analysis. BMC Bioinform., 9.","DOI":"10.1186\/1471-2105-9-559"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Ni, M., Wang, H., Xue, F., Luo, C., Wu, X., Liang, S., Li, C., Chen, T., Hong, L., and Zhang, J. (2026). Methane inhalation during ex vivo lung perfusion protects donor lungs after cardiac death via modulation of MAPK-related inflammatory and oxidative pathways. J. Heart Lung Transplant.","DOI":"10.1016\/j.healun.2026.05.027"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2365","DOI":"10.21037\/jtd-23-1809","article-title":"Subnormothermic ex vivo lung perfusion possibly protects against ischemia-reperfusion injury via the mTORC-HIF-1\u03b1 pathway","volume":"16","author":"Suh","year":"2024","journal-title":"J. Thorac. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s12931-025-03151-7","article-title":"Activation of Nrf2 pathway by 4-Octyl itaconate enhances donor lung function in cold preservation settings","volume":"26","author":"Gao","year":"2025","journal-title":"Respir. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e70965","DOI":"10.1111\/jcmm.70965","article-title":"HIF1\u03b1 Attenuated the Lung Ischemia\u2013Reperfusion Injury by Activating the miR-485\/Notch1 Signalling","volume":"30","author":"Dai","year":"2026","journal-title":"J. Cell. Mol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/j.molmed.2026.06.005","article-title":"Targeting ferroptosis halts graft deterioration in transplantation","volume":"32","author":"Mo","year":"2026","journal-title":"Trends Mol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Nyk\u00e4nen, A.I., Mariscal, A., Duong, A., Ali, A., Takahagi, A., Bai, X., Zehong, G., Joe, B., Takahashi, M., and Chen, M. (2024). Lung transplant immunomodulation with genetically engineered mesenchymal stromal cells\u2014Therapeutic window for interleukin-10. Cells, 13.","DOI":"10.3390\/cells13100859"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"102140","DOI":"10.1016\/j.xcrm.2025.102140","article-title":"Targeting mitochondrial complex I of CD177+ neutrophils alleviates lung ischemia-reperfusion injury","volume":"6","author":"Wu","year":"2025","journal-title":"Cell Rep. Med."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Sabashnikov, A., Agrawal, S., Zych, B., Krasivskyi, I., Abbas, S.H., Fungai, D., Williams, T., Thakuria, L., Aswani, A., and Osman, M. (2025). Selective Removal of Neutrophil Extracellular Traps (NETs) Combined with Ex Vivo Lung Perfusion (EVLP): Current Evidence and Future Perspectives. J. Clin. Med., 14.","DOI":"10.3390\/jcm14228136"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e173716","DOI":"10.1172\/jci.insight.173716","article-title":"CCR5 drives NK cell\u2013associated airway damage in pulmonary ischemia-reperfusion injury","volume":"8","author":"Santos","year":"2023","journal-title":"JCI Insight"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e170118","DOI":"10.1172\/JCI170118","article-title":"B cells mediate lung ischemia\/reperfusion injury by recruiting classical monocytes via synergistic B cell receptor\/TLR4 signaling","volume":"134","author":"Farahnak","year":"2024","journal-title":"J. Clin. Investig."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.jtcvs.2020.08.008","article-title":"Cell-free DNA in human ex vivo lung perfusate as a potential biomarker to predict the risk of primary graft dysfunction in lung transplantation","volume":"162","author":"Kanou","year":"2021","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e158002","DOI":"10.1172\/jci.insight.158002","article-title":"Donor IL-17 receptor A regulates LPS-potentiated acute and chronic murine lung allograft rejection","volume":"8","author":"Watanabe","year":"2023","journal-title":"JCI Insight"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e1815","DOI":"10.1097\/TP.0000000000005793","article-title":"Targeting Sphingosine-1-Phosphate Receptor 1 Protects Pulmonary Vascular Endothelial Integrity During Human Ex Vivo Lung Perfusion","volume":"110","author":"Gilmour","year":"2026","journal-title":"Transplantation"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Schiavon, M., Bennett, D., Boffini, M., Carillo, C., Dell\u2019aMore, A., Fumagalli, J., Luzzi, L., Pettenuzzo, T., Rosso, L., and Scappin, J. (2025). Use of Normothermic Perfusion Machines in Lung Transplantation: Consensus Statement of the Italian Society of Organ and Tissues Transplantation Group with DELPHI Method. Transpl. Int., 38.","DOI":"10.3389\/ti.2025.14762"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"ezaf390","DOI":"10.1093\/ejcts\/ezaf390","article-title":"Short-Term Outcomes After Lung Transplantation Using Grafts Preserved at 10 \u00b0C: A Single-Centre Study","volume":"67","author":"Orlandi","year":"2025","journal-title":"Eur. J. Cardio-Thorac. Surg."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Cui, E.Y., Gouchoe, D.A., Satija, D., Walsh, M.G., Gou, A., Alvarez, A.V., Henn, M.C., Ganapathi, A.M., Choi, K., and Whitson, B.A. (2026). Outcomes of Donation After Circulatory Death Lung Transplantation in the United States Based on Procurement Strategies: A United Network for Organ Sharing Analysis. Transplantation, ahead of print.","DOI":"10.1097\/TP.0000000000005803"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e70135","DOI":"10.1111\/ctr.70135","article-title":"Use of Normothermic Regional Perfusion in Circulatory Death Donors for Lung Transplantation in the United States","volume":"39","author":"Williams","year":"2025","journal-title":"Clin. Transplant."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1016\/j.healun.2026.03.021","article-title":"Twenty-four\u2013hour hypothermic oxygenated perfusion preserves graft viability in a porcine donation after circulatory death and donation after brain death heart transplant model","volume":"45","author":"Thomassen","year":"2026","journal-title":"J. Heart Lung Transplant."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1093\/ejcts\/ezab121","article-title":"Post-transplant outcomes of standard and extended criteria donation after circulatory death donor lungs categorized by donation after brain death lung criteria","volume":"60","author":"Tanaka","year":"2021","journal-title":"Eur. J. Cardio-Thorac. Surg."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Pergolizzi, C., Lazzeri, C., Marianello, D., Biuzzi, C., Irene, C., Puddu, A., Bargagli, E., Bennett, D., Catelli, C., and Luzzi, L. (2025). Strategies for Maximising Lung Utilisation in Donors After Brain and Cardiac Death: A Narrative Review. J. Clin. Med., 14.","DOI":"10.20944\/preprints202506.1635.v1"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"100027","DOI":"10.1016\/j.jhlto.2023.100027","article-title":"Ex vivo lung perfusion moderates gene expression differences between cardiac death and brain death donor lungs","volume":"3","author":"Allen","year":"2024","journal-title":"JHLT Open"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/9\/1127\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T04:25:21Z","timestamp":1789705521000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/9\/1127"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,16]]},"references-count":49,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["genes17091127"],"URL":"https:\/\/doi.org\/10.3390\/genes17091127","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,16]]}}}