Targeting RNA-binding motif protein 39 for arginine reduction: unveiling metabolic vulnerability in arginine-dependent liver cancer.

Cancer is increasingly acknowledged as a metabolic disease, characterized by metabolic reprogramming as its hallmark. However, the precise mechanisms behind this phenomenon and the factors contributing to tumorigenicity are still poorly understood. In a recent publication in Cell , Mossmann and colleague reported a study unveiling arginine as a molecule with second messenger-like properties that reshapes metabolism to facilitate the tumor development in hepatocellular carcinoma (HCC). Their research revealed that the RNA-binding motif protein 39 (RBM39)-mediated increase in asparagine synthesis results in increased arginine uptake. This establishes a positive feedback loop that sustains elevated levels of arginine and facilitates oncogenic metabolic reprogramming. Additionally, Mossmann et al. demonstrated that depleting RBM39 with indisulam effectively disrupts the proto-oncogenic metabolic reprogramming in HCC. This discovery presents a novel treatment strategy for arginine-dependent liver cancers.