Research Articles:
Cell Stress, Vol. 10, No. 1, pp. 1 - 8; doi: 10.15698/cst2026.01.314
Reversal of Cushing syndrome by antibody-mediated neutralization of ACBP/DBI
1 Université Paris Cité, Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Sorbonne Université, Paris, France. 2 Université Paris Saclay, Metabolomics and Cell Biology Platforms, UMS AMMICa, Gustave Roussy Institut, Villejuif, France. 3 Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre, Paris, France. 4 Department of Hematology/Institute of Hematology, West China Hospital, Sichuan University, Chengdu, China. 5 Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
a Equally contributed.
Keywords: endozepin, hypercortisolism, neuroendocrine, obesity
Received originally: 01/09/2025 Received in revised form: 10/12/2025
Accepted: 11/12/2025
Published: 26/01/2026
Correspondence:
Guido Kroemer, kroemer@orange.fr
Isabelle Martins, isabelle.martins@inserm
Conflict of interest statement: HP, IM and GK are the inventors of patents covering the therapeutic utility of ACBP/DBI neutralization. OK is a scientific co-founder of Samsara Therapeutics. IM is a consultant for Osasuna Therapeutics. GK has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Sutro, Tollys, and Vascage. GK is on the Board of Directors of the Bristol Myers Squibb Foundation France. GK is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. GK is in the scientific advisory boards of Hevolution, Institut Servier, and Rejuveron Life Sciences/Centenara Labs AG. GK is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis and metabolic disorders. Among these patents, one "Methods for weight reduction" (US11905330B1) is relevant to this study. GK’s brother, Romano Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. GK's wife, Laurence Zitvogel, has held research contracts with Glaxo Smyth Kline, Incyte, Lytix, Kaleido, Innovate Pharma, Daiichi Sankyo, Pilege, Merus, Transgene, 9 m, Tusk and Roche, was on the on the Board of Directors of Transgene, is a cofounder of everImmune, and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. The funders had no role in the design of the study, in the writing of the manuscript, or in the decision to publish the results.
Please cite this article as: Zhe Shen, Hui Pan, Xiaolian Deng, Oliver Kepp, Isabelle Martins, Guido Kroemer (2026). Reversal of Cushing syndrome by antibody-mediated neutralization of ACBP/DBI. Cell Stress 10: 1-8. doi: 10.15698/cst2026.01.314
Abstract
Cushing syndrome (CS) is caused by an increase in endogenous or exogenous glucocorticoids, leading to major alterations in body composition, including visceral obesity, sarcopenia, osteoporosis, type 2 diabetes, and dyslipidemia. Cardiovascular complications resulting from CS are often lethal. We previously demonstrated that CS induced by oral corticosterone (CORT) supplementation in mice can be prevented by inhibition of the peptide hormone acyl-CoA binding protein (ACBP), encoded by the gene diazepam binding inhibitor (DBI). Here, we investigated whether ACBP/DBI inhibition could be used to treat, rather than prevent, CS. To this end, we initiated treatment with anti-ACBP/DBI monoclonal antibodies (mAbs) in mice three weeks after the start of CORT supplementation, when hyperphagia and body weight gain were already established. Two anti-ACBP/DBI mAbs, 7G4a (specific for mouse ACBP/DBI only) and 82 (which recognizes both mouse and human ACBP/DBI), were able to normalize food intake and halt weight gain in mice under continuous CORT treatment. In addition, both mAbs attenuated CORT-induced sarcopenia, adiposity in inguinal, perigonadal, and visceral fat depots, and fully restored metabolic parameters, including insulinemia, free fatty acids, triglycerides, and liver transaminases. In conclusion, neutralization of ACBP/DBI may serve as an effective therapeutic strategy for the treatment of established CS.
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AUTHOR CONTRIBUTIONS
H.P. and Z.S. performed most of the in vitro and in vivo experiments. X.D. contributed to in vivo experiments. O.K. provided support for preclinical evaluation. G.K. conceived the project and designed the study. G.K. and I.M. supervised the project and wrote the manuscript with input from all other authors.
ACKNOWLEDGMENTS
GK is supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR-22-CE14-0066 VIVORUSH, ANR-23-CE44-0030 COPPERMAC, ANR-23-R4HC-0006 Ener-LIGHT); Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Fondation pour la Recherche Médicale (FRM); European Research Council Advanced Investigator Award (ERC-2021-ADG, Grant No. 101052444; project acronym: ICD-Cancer, project title: Immunogenic cell death (ICD) in the cancer-immune dialogue); The ERA4 Health Cardinnov Grant Ener-LIGHT; European Union Horizon 2020 research and innovation programs Oncobiome (grant agreement number: 825410, Project Acronym: ONCOBIOME, Project title: Gut OncoMicrobiome Signatures [GOMS] associated with cancer incidence, prognosis and prediction of treatment response, Prevalung (grant agreement number 101095604, Project Acronym: PREVALUNG EU, project title: Biomarkers affecting the transition from cardiovascular disease to lung cancer: towards stratified interception), Neutrocure (grant agreement number 861878 : Project Acronym: Neutrocure ; project title: Development of “smart” amplifiers of reactive oxygen species specific to aberrant polymorphonuclear neutrophils for treatment of inflammatory and autoimmune diseases, cancer and myeloablation); National support managed by the Agence Nationale de la Recherche under the France 2030 programme (reference number 21-ESRE-0028, ESR/Equipex+ Onco-Pheno-Screen); Hevolution Network on Senescence in Aging (reference HF-E Einstein Network); Institut National du Cancer (INCa); Institut Universitaire de France; PAIR-Obésité INCa_18713, the RHUs Immunolife and LUCA-pi (ANR-21-RHUS-0017 and ANR-23-RHUS-0010, both dedicated to France Relance 2030); Seerave Foundation; SIRIC Cancer Research and Personalized Medicine (CARPEM, SIRIC CARPEM INCa-DGOS-Inserm-ITMO Cancer_18006 supported by Institut National du Cancer, Ministère des Solidarités et de la Santé and INSERM). This study contributes to the IdEx Université de Paris Cité ANR-18-IDEX-0001. OK is supported by Association pour la recherche sur le cancer (ARC), Institut National du Cancer (INCa) and the European Innovation Council (EIC). ZS is supported by the China Scholarship Council (CSC, file No. 202308330135). H.P. is supported by the National Natural Science Foundation of China (No. 82504843 and 82570245).
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Reversal of Cushing syndrome by antibody-mediated neutralization of ACBP/DBI by Shen et al. is licensed under a Creative Commons Attribution 4.0 International License.
