ACBP: a poor-prognosis biomarker in sepsis and a target for disease mitigation

Septic shock 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 outcomes in sepsis. ACBP/DBI was elevated in the plasma of septic patients, correlating with organ dysfunction and 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 enhancing pathogen clearance, dampening cytokine storms, and preserving organ function. Notably, ACBP/DBI inhibition could be favorably combined with glucocorticoids, enhancing survival and reversing transcriptional and metabolic signatures of septic shock across spleen, liver, heart, and kidney. These findings position ACBP/DBI as a mechanistic amplifier of sepsis pathophysiology and propose its neutralization—alone or combined with corticosteroids—as a promising therapeutic strategy to interrupt the fatal trajectory of septic shock.