Integrated single-cell and clinical transcriptomic analysis identifies blunted glycolytic activation as a hallmark of maladaptive repair in renal ischemia-reperfusion

Article Article scientifique Article Integrated single-cell and clinical transcriptomic analysis identifies blunted glycolytic activation as a hallmark of maladaptive repair in renal ischemia-reperfusion eng 2025-08-28 2025-12 author Torck Alexandre Department of Intensive Care Medicine, Fribourg Hospital, Fribourg, Switzerland. 804724 author Sangla Frédéric Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium. 910074 author Quintard Hervé 0000-0002-3870-6370 Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium. 951770 Département d'anesthésiologie, pharmacologie et soins intensifs (APSIC) author Naesens Maarten Division of Intensive Care Medicine, Department of Anesthesiology, Clinical Pharmacology, Critical Care and Emergency Medicine, Geneva University Hospital, Geneva, Switzerland. author Legouis David 0000-0002-2924-9737 Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.,Laboratory of Nephrology, Department of Physiology and Cell Metabolism, University of Geneva, Geneva, Switzerland. 883952 Département d'anesthésiologie, pharmacologie et soins intensifs (APSIC) 2549400 10.1080/0886022X.2025.2549400 40878031 0886-022X PMC12404070 https://www.tandfonline.com/doi/10.1080/0886022X.2025.2549400 Acute kidney injury (AKI) is a common and increases risk of chronic kidney disease (CKD). While mitochondrial dysfunction drives maladaptive repair, the role of glycolysis in renal recovery remains unclear. Here, we integrated single-cell transcriptomic data from mouse models with clinical transcriptomic and functional data from kidney transplant recipients to investigate how glycolysis influences epithelial repair. Trajectory inference and metabolic flux estimation revealed divergent cellular fates: cell with active glycolysis achieved recovery, while those with blunted glycolysis followed, maladaptive paths. These results were confirmed in an independent single-cell dataset and validated clinically in reperfusion biopsies. A machine-learning model trained on clinical parameters identified patients with underactive glycolysis at reperfusion; this subgroup showed impaired long-term recovery. Although causality is unproven, early glycolytic activation appears linked to regenerative repair. Glycolysis thus emerges as both a biomarker of epithelial fate and a potential therapeutic target to limit CKD progression. AKI Glycolysis Metabolism Transplantation Glycolysis / genetics Animals Mice Humans Reperfusion Injury / metabolism Reperfusion Injury / pathology Reperfusion Injury / genetics Single-Cell Analysis Acute Kidney Injury / metabolism Acute Kidney Injury / pathology Acute Kidney Injury / genetics Kidney Transplantation / adverse effects Disease Models, Animal Kidney / pathology Kidney / metabolism Kidney / blood supply Renal Insufficiency, Chronic / etiology Renal Insufficiency, Chronic / pathology Gene Expression Profiling Machine Learning Male Transcriptome Female Dewey 612 Dewey 617 63 Département d'anesthésiologie, pharmacologie, soins intensifs et urgences 229 134 Département de physiologie cellulaire et métabolisme 21C false Renal failure 47 1 cc372dff-6eb7-425f-b4a9-1ff7b7eee138 Article (Published version) Public Integrated_single-cell_and_clinical.pdf 2817181 application/pdf CC BY-4.0 86b57061a1fc3b549acc8d18347b78a4851f40fa3ee0c925a43d683c4335b4bc openAccess Faculté de médecine / Section de médecine clinique / Département d'anesthésiologie, pharmacologie, soins intensifs et urgences Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme

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Integrated single-cell and clinical transcriptomic analysis identifies blunted glycolytic activation as a hallmark of maladaptive repair in renal ischemia-reperfusion	Renal failure			2025	23	137

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Torck, Alexandre