Full-Body Transcriptome Uncovers Hepatic Gluconeogenesis and PDK3 Upregulation as a Key Driver of Cancer Cachexia

Cachexia, a severe wasting syndrome characterized by tumor-induced metabolic dysregulation, is a leading cause of death in cancer patients, yet its underlying mechanisms remain poorly understood. We performed a longitudinal full-body single-nuclei resolution transcriptome analysis in a Drosophila model of cancer cachexia to capture interorgan dysregulations. Our study revealed that the tumor-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 regulation of their orthologs Pck1 and Pdk3 by IL-6/JAK-STAT signaling. Elevated expression of these genes in fly, mouse, and patients correlates with poor prognosis, and hepatic expression of Pdk3 emerges as a novel mechanism contributing to metabolic dysfunction in cancer cachexia. This study highlights the conserved nature of tumor-induced metabolic disruptions and identifies new therapeutic targets to mitigate cachexia in cancer patients.