Inosine suppresses liver A-to-I RNA editing to promote cancer-associated cachexia in a riboswitch-like manner

Cancer-associated cachexia (CAC) is a devastating syndrome and a major cause of morbidity and mortality in advanced cancer patients while liver is emerging as a key organ during CAC progression1. However, how tumor dysregulates liver function to promote CAC remains largely unknown. Here, we employ NMR spectrometry to detect that the elevation of 13C-inosine availability, attributed to the tumor-induced cytosolic 5'-nucleotidase II (NT5C2) protein accumulation, decreases the abundance of adenosine deaminase act on RNA 1 p150 isoform in a riboswitch-like manner. Intriguingly, reduced liver A-I mRNA editome enhances the stability of Cathepsin L mRNA to aggravate liver autophagy, triggering the secretion of serum amyloid A1, while CTSL-/- mice fail to develop cachectic phenotype upon inosine treatment. Strikingly, NT5C2 inhibitor CRCD2, a frontline leukemia treatment drug, greatly attenuates CAC progression. Conclusively, our finding reveals that inosine-mediated liver A-to-I mRNA editome alteration promotes CAC progression in a riboswitch-like manner, shedding light on the clinical applications for early CAC diagnosis and intervention.