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 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<sub>4</sub>) 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.

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Publication Details

Journal
Cell Reports Medicine
Published
2025-07-01
DOI
https://doi.org/10.1016/j.xcrm.2025.102232
Citations
5
Primary Topic
Ferroptosis and cancer prognosis
Type
article
Field-Weighted Citation Impact
7.59
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article

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

Fanny Aprahamian, Sabine Colnot, Jonathan Pol, Flavia Lambertucci et al.
5 citations
Cell Reports Medicine
Ferroptosis and cancer prognosis
7.59
article

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

Fanny Aprahamian, Sabine Colnot, Jonathan Pol, Flavia Lambertucci, Jean‐Charles Nault, Ester Gloria Saavedra Díaz, María Pérez-Lanzón, Uxía Nogueira-Recalde, Sylvie Lachkar, Christophe Klein, Omar Motiño, Manuela Lizarralde-Guerrero, Claudia Campani, Yanbing Dong, Jessica Zucman‐Rossi, Oliver Kepp, Li Sun, Vincent Carbonnier, Chantal Desdouets, Lucie Poupel, Laurence Zitvogel, Guido Kroemer, Léa Montégut, Isabelle Martins, Maria Chiara Maiuri, Long Pan, Federica Rossin, Gerasimos Anagnostopoulos, Sylvère Durand, Hui Chen, Hui Pan, Liwei Zhao, Peng Liu, Sijing Li, Alexandra Cerone, Mauro Piacentini, Enfu Xue
article en
5 citations

Abstract

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<sub>4</sub>) 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.

Cell Reports MedicineVol. 6(7)
Universidade da Coruña (ES), University of Rome Tor Vergata (IT), Centre National de la Recherche Scientifique (FR), Inserm (FR), China Pharmaceutical University (CN), Institut Universitaire de France (FR), Université Paris Cité (FR), Université Paris-Saclay (FR), Institut Gustave Roussy (FR), Sorbonne Université (FR), Universidad Fernando Pessoa Canarias (ES), Université Sorbonne Paris Nord (FR), Sorbonne Paris Cité (FR), Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani (IT), Centre de Recherche des Cordeliers (FR), Assistance Publique – Hôpitaux de Paris (FR), Hôpital Européen Georges-Pompidou (FR), Federico II University Hospital (IT), Hôpital Avicenne (FR), University of Florence (IT), University of Naples Federico II (IT)
Good health and well-being
Openalex Percentile: Top 3%
Ferroptosis and cancer prognosis
7.59
DOIOpen Access PDFOpenAlex
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