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Herein, we combine human multi-omics, mechanistic mouse models and controlled cell death assays to identify cell death\u2013driven 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 &gt;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\u2013driven 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.<\/jats:p>","DOI":"10.1038\/s41418-026-01775-w","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T16:53:20Z","timestamp":1780505600000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Cell death\u2013induced release of the pro-aging protein acyl CoA binding protein (ACBP) into the circulation"],"prefix":"10.1038","author":[{"given":"Yan","family":"Rong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia","family":"Lambertucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaning","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Carbonnier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1260-8617","authenticated-orcid":false,"given":"Hui","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanbing","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Mingoia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sijing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3858-0966","authenticated-orcid":false,"given":"Omar","family":"Moti\u00f1o","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4778-4757","authenticated-orcid":false,"given":"L\u00e9a","family":"Mont\u00e9gut","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5278-8966","authenticated-orcid":false,"given":"Adrien","family":"Joseph","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucille","family":"Ferret","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ester Gloria","family":"Saavedra D\u00edaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephane","family":"Isnard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Pierre","family":"Routy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4893-6505","authenticated-orcid":false,"given":"Mojgan","family":"Djavaheri-Mergny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Castedo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5583-106X","authenticated-orcid":false,"given":"Alexander","family":"Fuerlinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5042-9054","authenticated-orcid":false,"given":"Mahmoud","family":"Abdellatif","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Chiara","family":"Maiuri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0885-613X","authenticated-orcid":false,"given":"Isabelle","family":"Martins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9334-4405","authenticated-orcid":false,"given":"Guido","family":"Kroemer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,3]]},"reference":[{"key":"1775_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2019.06.008","volume":"208","author":"MC Tonon","year":"2020","unstructured":"Tonon MC, Vaudry H, Chuquet J, Guillebaud F, Fan J, Masmoudi-Kouki O, et al. 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GK has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Sutro, Tollys and Vascage. GK is on the Board of Directors of the Bristol Myers Squibb Foundation France. GK is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. GK is in the scientific advisory boards of Hevolution, Institut Servier and Rejuveron Life Sciences\/Centenara Labs AG. GK is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis and metabolic disorders. Among these patents, one \u201cMethods for weight reduction\u201d (US11905330B1) is relevant to this study. GK\u2019s brother, Romano Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. GK\u2019s wife, Laurence Zitvogel, has held research contracts with Glaxo Smyth Kline, Incyte, Lytix, Kaleido, Innovate Pharma, Daiichi Sankyo, Pilege, Merus, Transgene, 9\u2009m, Tusk and Roche, was on the Board of Directors of Transgene, is a cofounder of everImmune and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. The funders had no role in the design of the study, in the writing of the manuscript or in the decision to publish the results.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}