Neutralization of acyl coenzyme A binding protein for the experimental prevention and treatment of hepatocellular carcinoma

Acyl coenzyme A binding protein (ACBP encoded by diazepam binding inhibitorDBI) is involved in non-malignant liver diseases. Here, we show that DBI mRNA and circulating ACBP/DBI levels are increased in patients with hepatocellular carcinoma (HCC). We investigated its role in hepatocarcinogenesis in mice, inhibiting ACBP/DBI by three methods: (1) inducible whole-body or liver-specific knockout of DBI, (2) a point mutation of the ACBP/DBI receptor (GABRG2), and (3) induction of autoantibodies neutralizing ACBP/ DBI. ACBP/DBI plays a major pro-carcinogenic role in HCC induced by intrahepatic transplantation of HCC cell lines, transgenic co-expression of the two oncogenes Myc and Ctnnb1, and chronic challenge with a Western-style diet together with either carbon tetrachloride (CCl4) or diethylnitrosamine. ACBP/ DBI inhibition normalizes HCC-associated gene expression, reducing oncogenic alterations in cell cycle-, immunomodulatory-, and ferroptosis-regulatory genes. ACBP/DBI inhibition increases HCC responses to PD-1 blockade and sensitizes HCC to the therapeutic induction of ferroptosis. Hence, ACBP/DBI constitutes an actionable target involved in HCC pathogenesis.