Proteomics on Inhibition of ceramide synthesis in the context of cachexia

Cachexia is a metabolic wasting syndrome affecting most of cancer patients. Disturbed lipid metabolism is a cachexia hallmark, and our previous work has identified increased levels of circulating ceramides, bioactive lipids with established functions in metabolic diseases, as biomarkers for cachexia in mouse models and patients. Here, we demonstrate that elevated ceramides in cachexia arise from increased liver synthesis. We show that ceramides directly contribute to impaired mitochondrial function and energy homeostasis in cachexia target tissues. Targeting ceramide synthesis using myriocin, an approved compound targeting the key synthesis enzyme serine palmitoyltransferase (SPT), improved muscle atrophy in cachectic mice. Lastly, we demonstrate that key enzymes involved in ceramide production are also elevated in livers, but not other organs, of patients with cancer cachexia, correlating with disease severity. Our data place ceramides as novel contributors to metabolic dysfunction in cachexia and highlight the suitability of the ceramide synthesis pathway for therapeutic targeting.