2. Academic Validation
  3. Cell death-induced release of the pro-aging protein acyl CoA binding protein (ACBP) into the circulation

Cell death-induced release of the pro-aging protein acyl CoA binding protein (ACBP) into the circulation

  • Cell Death Differ. 2026 Jun 3. doi: 10.1038/s41418-026-01775-w.
Yan Rong 1 2,  Flavia Lambertucci 1,  Yaning Yang 1,  Vincent Carbonnier 1,  Hui Chen 1,  Yanbing Dong 1 2,  Silvia Mingoia 1,  Sijing Li 1,  Omar Motiño 1 3,  Léa Montégut 1,  Adrien Joseph 4 5,  Lucille Ferret 1,  Ester Gloria Saavedra Díaz 1 6,  Stephane Isnard 7 8,  Jean-Pierre Routy 7 8 9,  Mojgan Djavaheri-Mergny 1,  Maria Castedo 1,  Alexander Fuerlinger 10 11,  Mahmoud Abdellatif 1 10 11,  Maria Chiara Maiuri 1 12,  Isabelle Martins 13,  Guido Kroemer 14 15 16
Affiliations

Affiliations

  • 1 Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université Paris Cité, Sorbonne Université, Paris, France.
  • 2 Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre, Paris, France.
  • 3 Unidad de Excelencia, Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid - CSIC, Valladolid, Spain.
  • 4 Intensive Care Unit, University Hospital Ambroise Pare, GHU Paris-Saclay, AP-HP, Boulogne-Billancourt, France.
  • 5 Inserm U1173, Laboratory of Infection and Inflammation, University Versailles Saint Quentin - University Paris Saclay, Guyancourt, France.
  • 6 Departamento de Bioquímica y Biología Molecular, Fisiología, Genética e Inmunología, Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.
  • 7 Infection and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
  • 8 Chronic Viral Illness Service, McGill University Health Centre, Montreal, QC, Canada.
  • 9 Division of Hematology, McGill University Health Centre, Montreal, QC, Canada.
  • 10 Department of Cardiology, Medical University of Graz, Graz, Austria.
  • 11 BioTechMed, Graz, Austria.
  • 12 Department of Molecular Medicine and Medical Biotechnologies, University of Napoli Federico II, Naples, Italy.
  • 13 Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université Paris Cité, Sorbonne Université, Paris, France. [email protected].
  • 14 Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université Paris Cité, Sorbonne Université, Paris, France. [email protected].
  • 15 Université Paris-Saclay, INSERM US23/CNRS UAR 3655, Metabolomics and Cell Biology Platforms, UMS AMMICa, Institut Gustave Roussy, Villejuif, France. [email protected].
  • 16 Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France. [email protected].
PMID: 42236908 DOI: 10.1038/s41418-026-01775-w
Abstract

Acyl-CoA-binding protein (ACBP, encoded by diazepam binding inhibitor, DBI) is an abundant intracellular regulator of lipid metabolism that also circulates systemically, yet the mechanisms governing its release and its relationship to organ injury remain unresolved. Herein, we combine human multi-omics, mechanistic mouse models and controlled cell death assays to identify cell death-driven liberation of intracellular ACBP/DBI as a unifying mechanism underlying its elevation in disease. In a cohort of 1198 hospitalized adults, among whom 75% were acutely infected by SARS-CoV-2, plasma ACBP/DBI tightly correlated with inflammatory markers and biochemical signatures of cardiac, hepatic, renal, metabolic and hematologic dysfunction. SomaScan proteomics further revealed that ACBP/DBI co-varies with organ-enriched proteins, particularly those originating from skeletal muscle and pancreas, implicating tissue injury as a major determinant of its circulating abundance. Multiple forms of acute organ damage in mice, including hepatic or renal ischemia-reperfusion, bile duct ligation, pancreatitis and rhabdomyolysis, triggered rapid and robust increases in plasma ACBP/DBI. Using defined in vitro paradigms, we demonstrate that Apoptosis, Ferroptosis and Necroptosis each cause loss of intracellular ACBP/DBI and its release upon plasma membrane permeabilization, independent of the upstream lethal pathway. These mechanistic insights translated in vivo: hepatocyte Apoptosis, Ferroptosis and Necroptosis each elevated circulating ACBP/DBI in a manner attenuated by pathway-specific inhibitors. Finally, meta-analysis of >100,000 individuals across diverse populations revealed that elevated plasma ACBP/DBI consistently associates with systemic and organ-specific disease and predicts future morbidity. Together, our findings identify cell death-driven ACBP/DBI release as a conserved mechanism linking organ injury to increased plasma ACBP/DBI, positioning this molecule as an integrative biomarker of tissue damage across species, organs, and cell death modalities.

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