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

作者：Sijing Li, Omar Motiño, Flavia Lambertucci, Jonathan Pol, Hui Chen, Long Pan, Sylvère Durand, Federica Rossin, Claudia Campani, Lucie Poupel, Christophe Klein, Léa Montégut, María Pérez-Lanzón, Gerasimos Anagnostopoulos, Uxía Nogueira-Recalde, Alexandra Cerone, Fanny Aprahamian, Yanbing Dong, Manuela Lizarralde-Guerrero, Enfu Xue, Peng Liu, Liwei Zhao, Hui Pan, Vincent Carbonnier, Sylvie Lachkar, Ester Gloria Saavedra Díaz, Li Sun, Chantal Desdouets, Sabine Colnot, Oliver Kepp, Isabelle Martins, Laurence Zitvogel, Mauro Piacentini, Jean‐Charles Nault, Maria Chiara Maiuri, Jessica Zucman‐Rossi, Guido Kroemer · 发表于：Cell Reports Medicine · 年份：2025 · DOI：10.1016/j.xcrm.2025.102232 · 被引用次数：7 · 研究领域：Ferroptosis and cancer prognosis、Epigenetics and DNA Methylation、Drug Transport and Resistance Mechanisms

Acyl coenzyme A binding protein (ACBP encoded by diazepam binding inhibitor DBI ) 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 (CCl 4 ) 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.