Acyl-CoA-binding protein (ACBP): a poor-prognosis biomarker in sepsis and a target for disease mitigation.

Sepsis remains a major clinical challenge, with high mortality and long-term disability despite current interventions. Here, we identify the tissue hormone acyl-CoA-binding protein (ACBP), also known as diazepam-binding inhibitor (DBI), as a biomarker and driver of poor outcome in sepsis. ACBP/DBI was elevated in the plasma of septic patients and associated with organ dysfunction and increased mortality. In murine models of endotoxemia, Escherichia coli infection, and polymicrobial sepsis, genetic deletion or antibody-mediated neutralization of ACBP/DBI conferred robust protection by dampening cytokine storm and preserving organ function. Across these three models, neutralization of ACBP/DBI with monoclonal antibodies restored thermoregulation and reduced mortality. Mechanistically, ACBP/DBI inhibition enhanced resilience to lipopolysaccharide-induced sterile inflammation and improved bacterial clearance by macrophages and granulocytes in vivo and in vitro. These effects were observed in monomicrobial infection models and confirmed by high-dimensional immunophenotyping in a polymicrobial sepsis model. Notably, ACBP/DBI inhibition could be favorably combined with glucocorticoids, enhancing survival and reversing histopathological, transcriptional or metabolic signatures of septic shock across heart, kidney, liver, lung, spleen and plasma. These findings position ACBP/DBI as a mechanistic amplifier of sepsis pathophysiology and propose its neutralization, alone or in combination with corticosteroids, as a promising therapeutic strategy to interrupt the fatal trajectory of septic shock.