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

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.