Hepatic ceramide synthesis links systemic inflammation to organelle dysfunction in cancer
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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 CG5966 , which we named “ cancer-associated lipid mobilizer ( calm )”, and the ceramide synthase schlank in the fat body/liver, which rewires fat body lipid metabolism resulting in an autophagic-flux blockade. Genetic reduction of either CG5966 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.