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2025

Cell Rep Med. 2025 Jul 15;6(7):102232. doi: 10.1016/j.xcrm.2025.102232. Epub 2025 Jul 7.

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

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, Uxia 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

Université Paris Cité, Sorbonne Université, Inserm U1138, Centre de Recherche des Cordeliers, F-75006 Paris, France; Équipe Labellisée Par La Ligue Contre le Cancer, Institut Universitaire de France, Paris, France; Université Paris-Saclay, INSERM US23 / CNRS UAR 3655, Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France; Faculté de Médecine, Université de Paris Saclay, Kremlin Bicêtre, Paris, France. 2 Université Paris Cité, Sorbonne Université, Inserm U1138, Centre de Recherche des Cordeliers, F-75006 Paris, France; Équipe Labellisée Par La Ligue Contre le Cancer, Institut Universitaire de France, Paris, France; Université Paris-Saclay, INSERM US23 / CNRS UAR 3655, Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France. 3 Team "Functional Genomics of Solid Tumors", Centre de Recherche des Cordeliers, Inserm U1138, Université Paris Cité, Sorbonne Université, 75006 Paris, France. 4 Department of Biology, University of Rome 'Tor Vergata', Rome, Italy; National Institute for Infectious Diseases IRCCS "Lazzaro Spallanzani", 00133 Rome, Italy. 5 Team "Functional Genomics of Solid Tumors", Centre de Recherche des Cordeliers, Inserm U1138, Université Paris Cité, Sorbonne Université, 75006 Paris, France; Department of Experimental and Clinical Medicine, Internal Medicine and Hepatology Unit, University of Firenze, Florence, Italy. 6 CHICS, Centre de Recherche des Cordeliers, Inserm U1138, Université Paris Cité, Sorbonne Université, Paris, France. 7 Université Paris Cité, Sorbonne Université, Inserm U1138, Centre de Recherche des Cordeliers, F-75006 Paris, France; Équipe Labellisée Par La Ligue Contre le Cancer, Institut Universitaire de France, Paris, France; Université Paris-Saclay, INSERM US23 / CNRS UAR 3655, Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France; Grupo de Investigación en Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Fundación Profesor Novoa Santos, A Coruña, Spain. 8 Université Paris Cité, Sorbonne Université, Inserm U1138, Centre de Recherche des Cordeliers, F-75006 Paris, France; Équipe Labellisée Par La Ligue Contre le Cancer, Institut Universitaire de France, Paris, France; Université Paris-Saclay, INSERM US23 / CNRS UAR 3655, Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France; Departamento de Bioquímica y Biología Molecular, Fisiología, Genética e Inmunología, Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain. 9 Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China. 10 Team Genomic Instability, Metabolism, Immunity and Liver Tumorigenesis Laboratory, Equipe Labellisée LIGUE 2023, Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, Paris, France. 11 Team "Oncogenic functions of β-catenin Signaling in the Liver (ONCOLIV)", Centre de Recherche des Cordeliers, Equipe Labellisée Par La Ligue Contre le Cancer, Inserm U1138, Université Paris Cité, Sorbonne Université, Paris, France. 12 Gustave Roussy Cancer Center, ClinicoBiome, 94805 Villejuif, France; Université Paris Saclay, Faculty of Medicine, 94270 Kremlin Bicêtre, France; Inserm U1015, Equipe Labellisée Par La Ligue Contre le Cancer, 94800 Villejuif, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT), Gustave Roussy, 94805 Villejuif, France. 13 Team "Functional Genomics of Solid Tumors", Centre de Recherche des Cordeliers, Inserm U1138, Université Paris Cité, Sorbonne Université, 75006 Paris, France; Liver Unit, Avicenne Hospital, Paris-Seine-Saint-Denis Universitary Hospitals, AP-HP, Bobigny, France. 14 Université Paris Cité, Sorbonne Université, Inserm U1138, Centre de Recherche des Cordeliers, F-75006 Paris, France; Équipe Labellisée Par La Ligue Contre le Cancer, Institut Universitaire de France, Paris, France; Department of Molecular Medicine and Medical Biotechnologies, University of Napoli Federico II, 80131 Naples, Italy. 15 Team "Functional Genomics of Solid Tumors", Centre de Recherche des Cordeliers, Inserm U1138, Université Paris Cité, Sorbonne Université, 75006 Paris, France; Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France. 16 Université Paris Cité, Sorbonne Université, Inserm U1138, Centre de Recherche des Cordeliers, F-75006 Paris, France; Équipe Labellisée Par La Ligue Contre le Cancer, Institut Universitaire de France, Paris, France; Université Paris-Saclay, INSERM US23 / CNRS UAR 3655, Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France; Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.

Service type: Knockout mice

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 (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. Keywords: ACBP/DBI inhibition; HCC; MASH; anti-PD-1; ferroptosis; immunotherapy; obesity; proliferation.

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