Liu, Ying, Miao, Ting, Wang, Alice, Dantas, Ezequiel, Kim, Ah-Ram, Zhang, Zhongjie, Sun, Xiaomei, Binari, Richard, Asara, John M, Hu, Yanhui, Goncalves, Marcus D, Janowitz, Tobias, Perrimon, Norbert (October 2025) Hepatic ceramide synthesis links systemic inflammation to organelle dysfunction in cancer. bioRxiv. ISSN 2692-8205 (Submitted)
![[thumbnail of 10.1101.2025.10.01.679814.pdf]](https://repository.cshl.edu/style/images/fileicons/application_pdf.png) |
PDF
10.1101.2025.10.01.679814.pdf - Submitted Version Available under License Creative Commons Attribution. Download (21MB) |
Abstract
Paraneoplastic syndromes arise when tumor-derived cytokines reprogram distant organs. Although mediators such as Interleukin-6 have been implicated, how these signals impair host organ function remains incompletely defined. Here, we identify a cytokine-lipid axis that drives hepatic autophagy dysfunction. Specifically, in Drosophila , the gut tumor-derived interleukin-like cytokine Upd3 induces the expression of the triglyceride lipase CG5SCC , which we named " cancer-associated lipid mobilizer ( calm )", and the ceramide synthase schlank in the fat body. This upregulation rewires fat body lipid metabolism, resulting in an autophagic-flux blockade. Genetic reduction of either CG5SCC or schlank restores organelle homeostasis and mitigates paraneoplastic phenotypes. This mechanism is conserved in mammals: in mice, IL-6 upregulates the lipoprotein lipase Lpl and ceramide synthases which in turn trigger a hepatic autophagy-flux blockade; in humans, hepatic LPL and ceramide synthases expression correlates with poorer survival in hepatocellular carcinoma. Our findings position hepatic lipid metabolism rewiring, especially ceramide synthesis as a critical, conserved node coupling systemic inflammation to organelle dysfunction, and suggest this pathway as a possible therapeutic entry point for cancer-associated liver disorders.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders |
| CSHL Authors: | |
| Communities: | CSHL labs > Janowitz lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 16 October 2025 |
| Date Deposited: | 01 Dec 2025 14:27 |
| Last Modified: | 01 Dec 2025 14:27 |
| PMCID: | PMC12621733 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/42017 |
Actions (login required)
 |
Administrator's edit/view item |