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Morigny, P. ; Ji, H. ; Cussonneau, L.* ; Zorzato, S.* ; Kwon, Y.* ; Riols, F. ; Kaltenecker, D. ; Maier, A. ; Karthikaisamy, V. ; Corrà, S.* ; Krauss, T.* ; Seeliger, C.* ; Gillani, S.Q. ; Tissink, J.J. ; Lacas-Gervais, S.* ; Samanci, T.F. ; Maida, A. ; Terron Exposito, R. ; Trinca, A. ; von Toerne, C. ; Nogara, L.* ; Claussnitzer, M.* ; Prokopchuk, O.* ; Bachmann, J.* ; Berriel Diaz, M. ; Bindels, L.B.* ; Kuda, O.* ; Hauner, H.* ; Haid, M. ; Herzig, S. ; Viscomi, C.F.* ; Gilleron, J.* ; Zeigerer, A. ; Blaauw, B.* ; Rohm, M.

Inhibition of ceramide synthesis ameliorates body wasting in a cancer cachexia model.

J. Clin. Invest. 136:e194687 (2026)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Cachexia is a metabolic wasting syndrome affecting many patients with cancer, with poor survival outcomes. Disturbed lipid metabolism is a hallmark of cachexia, and our previous work has identified increased levels of circulating ceramides, which are bioactive lipids with adverse effects in metabolic diseases, as biomarkers for cachexia in mouse models and patients. Here, we investigated the role of ceramides on cachexia development using the well-established C26 colon carcinoma model. We demonstrated that elevated ceramides in cachexia arose from increased liver synthesis. We showed that ceramides directly contributed to impaired mitochondrial function and energy homeostasis in cachexia target tissues. Targeting ceramide synthesis using miRNA interference, or myriocin, an approved compound targeting the key synthesis enzyme serine palmitoyltransferase (SPT), improved markers of muscle atrophy in cachectic male mice. Importantly, we demonstrated that key enzymes involved in ceramide production were also elevated in livers, but not in other organs, of patients with cancer cachexia, correlating with disease severity. Our data place ceramides as contributors to metabolic dysfunction in cachexia and highlight the suitability of the ceramide synthesis pathway for therapeutic targeting.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Cancer ; Lipidomics ; Metabolism ; Mitochondria ; Oncology; Insulin-resistance; Sphingolipids; Metabolism; Obesity; Biosynthesis; Disease
ISSN (print) / ISBN 0021-9738
e-ISSN 1558-8238
Journal Journal of Clinical Investigation
Quellenangaben Volume: 136, Issue: 10, Pages: , Article Number: e194687 Supplement: ,
Publisher American Society of Clinical Investigation
Publishing Place 2015 Manchester Rd, Ann Arbor, Mi 48104 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Cancer (IDC)
CF Metabolomics & Proteomics (CF-MPC)
Grants . Agence Nationale de la Recherche Projet de Recherche Collaborative program
. French National Research Agency (ANR) through the Investments for the Future Labex SIGNALIFE
France
Bad Homburg, Germany