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Kaltenecker, D. ; Schmidt, S.F. ; Weber, P. ; Loft, A. ; Morigny, P. ; Machado, J. ; Geppert, J. ; Saul, K.B.* ; Benedikt-Kühnast, P. ; Molocea, C.-E. ; Scott, R.* ; Haase, K.* ; Martignoni, M.E.* ; Alfaro, A.J. ; Chow, K.K. ; Simoes Fernandez, E. ; Pinhata Otoch, J.* ; Lima, J.D.C.C.* ; Swanton, C.* ; Spielmann, N. ; Hrabě de Angelis, M. ; Elsner, M. ; Ertürk, A. ; Dyar, K.A. ; Rohm, M. ; Prokopchuk, O.* ; Jamal-Hanjani, M.* ; Seelaender, M.* ; Backs, J.* ; Herzig, S. ; Berriel Diaz, M.

Functional liver genomics identifies hepatokines promoting wasting in cancer cachexia.

Cell, DOI: 10.1016/j.cell.2025.06.039 (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
In cancer cachexia, the presence of a tumor triggers systemic metabolic disruption that leads to involuntary body weight loss and accelerated mortality in affected patients. Here, we conducted transcriptomic and epigenomic profiling of the liver in various weight-stable cancer and cancer cachexia models. An integrative multilevel analysis approach identified a distinct gene expression signature that included hepatocyte-secreted factors and the circadian clock component REV-ERBα as key modulator of hepatic transcriptional reprogramming in cancer cachexia. Notably, hepatocyte-specific genetic reconstitution of REV-ERBα in cachexia ameliorated peripheral tissue wasting. This improvement was associated with decreased levels of specific cachexia-controlled hepatocyte-secreted factors. These hepatokines promoted catabolism in multiple cell types and were elevated in cachectic cancer patients. Our findings reveal a mechanism by which the liver contributes to peripheral tissue wasting in cancer cachexia, offering perspectives for future therapeutic interventions.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Intact ; Rev-erb ; Adipose Tissue Wasting ; Cachexia ; Circadian Clock ; Hepatic Reprogramming ; Liver-secreted Factors ; Muscle Atrophy
ISSN (print) / ISBN 0092-8674
e-ISSN 1097-4172
Journal Cell
Publisher Cell Press
Publishing Place Cambridge, Mass.
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Cancer (IDC)
Institute of Experimental Genetics (IEG)
Institute for Tissue Engineering and Regenerative Medicine (ITERM)