Annotation: Cachexia is a debilitating wasting syndrome that drives high rates of morbidity and mortality among cancer patients. Although tumor–host interactions and maladaptive metabolic reprogramming are known to play major roles, their mechanisms remain incompletely understood. Here, we present a detailed picture of spatio-temporal metabolic alterations that occur during cachexia, combining untargeted metabolomics with ¹³C‑glucose tracing across a range of organs and tumors from male tumor-bearing mice at early, intermediate, and late disease stages. We identified one-carbon metabolism as a tissue-overarching pathway characteristic for metabolic wasting in mice, which is linked to inflammation, glucose hypermetabolism, and muscle atrophy. Notably, the same rewiring of one‑carbon metabolism was recapitulated in several additional mouse models of cachexia. Altogether, these findings establish a molecular framework for the coordinated, multi‑tissue metabolic response that underlies cancer‑induced cachexia, highlighting one‑carbon metabolism as a central, tissue-overarching driver of the wasting phenotype.

IPHYS contact: Kristýna Brejchová, Laboratory of Bioactive Lipids, IPHYS; kristyna.brejchova@fgu.cas.cz