| RRC ID |
83855
|
| Author |
Liu Y, Dantas E, Ferrer M, Miao T, Qadiri M, Liu Y, Comjean A, Davidson EE, Perrier T, Ahmed T, Hu Y, Goncalves MD, Janowitz T, Perrimon N.
|
| Title |
Hepatic gluconeogenesis and PDK3 upregulation drive cancer cachexia in flies and mice.
|
| Journal |
Nat Metab
|
| Abstract |
Cachexia, a severe wasting syndrome characterized by tumour-induced metabolic dysregulation, is a leading cause of death in people with cancer, yet its underlying mechanisms remain poorly understood. Here we show that a longitudinal full-body single-nuclei-resolution transcriptome analysis in a Drosophila model of cancer cachexia captures interorgan dysregulations. Our study reveals that the tumour-secreted interleukin-like cytokine Upd3 induces fat-body expression of Pepck1 and Pdk, key regulators of gluconeogenesis, disrupting glucose metabolism and contributing to cachexia. Similarly, in mouse cancer cachexia models, we observe IL-6-JAK-STAT-signalling-mediated induction of Pck1 and Pdk3 expression in the liver. Increased expression of these genes in fly, mouse, and human correlates with poor prognosis, and hepatic expression of Pdk3 emerges as a previously unknown mechanism contributing to metabolic dysfunction in cancer cachexia. This study highlights the conserved nature of tumour-induced metabolic disruptions and identifies potential therapeutic targets to mitigate cachexia in people with cancer.
|
| Volume |
7(4)
|
| Pages |
823-841
|
| Published |
2025-4-1
|
| DOI |
10.1038/s42255-025-01265-2
|
| PII |
10.1038/s42255-025-01265-2
|
| PMID |
40275022
|
| PMC |
PMC12021660
|
| MeSH |
Animals
Cachexia* / etiology
Cachexia* / genetics
Cachexia* / metabolism
Disease Models, Animal
Drosophila
Drosophila Proteins* / genetics
Drosophila Proteins* / metabolism
Gluconeogenesis* / genetics
Humans
Liver* / metabolism
Mice
Neoplasms* / complications
Neoplasms* / metabolism
Pyruvate Dehydrogenase Acetyl-Transferring Kinase* / genetics
Pyruvate Dehydrogenase Acetyl-Transferring Kinase* / metabolism
Up-Regulation
|
| Resource |
| Drosophila |
15009R-3 |
