ACBP/DBI neutralization for the prevention and treatment of malignant and non-malignant liver diseases

Abstract Acyl coenzyme A binding protein (ACBP), also known as diazepam binding inhibitor (DBI), suppresses autophagy, stimulates food intake, and regulates body composition. This tissue hormone contributes to the development of age-related diseases such as metabolic syndrome, cardiovascular disease, cancer, and osteoarthritis. ACBP/DBI also plays a key pathogenic role in liver disorders, including hepatocellular carcinoma (HCC). Circulating levels of ACBP/DBI are elevated in patients with histologically diagnosed steatosis, liver fibrosis or HCC, and correlate with disease severity. Moreover, the incidence of liver cancers increases in individuals receiving benzodiazepines, which act on the same binding sites of the GABA-A receptor as ACBP/DBI. In mice, inhibiting ACBP/DBI, via inducible knockout, mutation of its receptor (the γ2 subunit of the GABA-A receptor) or antibody-mediated neutralization, alleviates various liver conditions, including ischemia-reperfusion injury, bile duct obstruction, hepatotoxicity of acetaminophen, CCl 4 , ethanol, or concanavalin A, metabolic dysfunction-associated fatty liver disease, and HCC. Importantly, the anti-tumor effects of ACBP/DBI neutralization are not solely due to its hepatoprotective properties, as they persist in mouse models of HCC driven by oncogenes (e.g., β-catenin and MYC) or orthotopic injection of syngeneic liver cancer cells into immunocompetent hosts. Notably, hepatocellular carcinoma (HCC) is one of the few cancers in which elevated local ACBP/DBI expression is associated with poor clinical prognosis. In sum, ACBP/DBI functions as both a biomarker and a potential therapeutic target for malignant and non-malignant liver diseases.