Uridine Inhibits Hepatocellular Carcinoma Cell Development by Inducing Ferroptosis

Abstract

Uridine is a key metabolite used as a substrate for the production of DNA, RNA, and glucose, and it is mainly synthesized in the liver. Currently, it is not known whether uridine levels are altered in the tumor microenvironment of patients with hepatocellular carcinoma (HCC) and whether uridine can be a target for tumor therapy. In this study, the detection of genes associated with de novo uridine synthesis, carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, dihydroorotase (CAD) (n = 115), and dihydroorotate dehydrogenase (DHODH) (n = 115) in HCC tissues through tissue microarrays revealed that the expression of CAD and DHODH was higher in tumor compared with paraneoplastic tissues. Next, we collected tumor tissues from surgically resected HCC patients and the corresponding adjacent non-tumor tissues (n = 46) for LC–MS/MS assays. The results showed that the median and interquartile ranges of uridine content in non-tumor and tumor tissues were 640.36 (504.45–807.43) and 484.22 (311.91–626.73) nmol/g, respectively. These results suggest that uridine metabolism is disturbed in HCC patients. To further investigate whether uridine can be used as a tumor-therapeutic target, a series of high concentrations of uridine were incubated with HCC cells in vitro and in vivo. It was observed that uridine dose-dependently inhibited the proliferation, invasion, and migration of HCC cells by activating the ferroptosis pathway. Overall, these results reveal for the first time the range of uridine content in human HCC tissues and suggest that uridine may be a new target for HCC therapy.

Ferroptosis in Liver Disease: Natural Active Compounds and Therapeutic Implications

“…Together with mGPX4, DHODH constructs the antioxidant system of mitochondria, which withstands the tremendous pressure of mitochondrial membrane lipid peroxidation. Uridine, a key substrate for synthesizing DNA, RNA, and glucose, was shown to trigger ferroptosis in HCC cells and suppress the further development of HCC [ 68 ]. Uridine synthesis in tumor cells mainly depends on the de novo synthesis pathway [ 69 ].…”

“…Uridine synthesis in tumor cells mainly depends on the de novo synthesis pathway [ 69 ]. Interestingly, DHODH is one of the rate-limiting enzymes for de novo synthesis of uridine and its expression can be inhibited by high concentration of uridine in vitro, which may explain why uridine can induce ferroptosis in HCC cells [ 68 ]. However, the inhibitory effect of DHODH on ferroptosis is controversial because DHODH only functions at high concentrations that also effectively inhibit FSP1 [ 70 ].…”