Unveiling the pyrimidine metabolism: A key metabolic signature and NT5E as a potential target in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies due to the lack of effective therapeutic targets and treatments. Metabolic reprogramming is one core malignant feature of cancer; hence, targeting the metabolic pathway may be a new approach to treat ESCC. Metabolomic data of 94 paired ESCC tissues suggest that pyrimidine metabolism is prominently activated and indicates poor prognosis in ESCC. Additionally, public databases and results from ESCC patients demonstrate that NT5E, a key enzyme in pyrimidine metabolism, is remarkably higher in ESCC tissues compared with normal adjacent tissues. Furthermore, higher NT5E reveals worse prognosis in ESCC patients, while blocking NT5E significantly impeded the proliferation of ESCC cells through obstructing pyrimidine metabolism. Subsequently, we identified icaritin, a natural flavonoid compound, which could be a potential NT5E inhibitor with significant suppression of ESCC both in vitro and in vivo . Metabolomic analysis revealed that icaritin markedly interfered with pyrimidine metabolism in ESCC cells and notably down-regulated NT5E through post-translational modification. Further investigations revealed that icaritin could directly bind to NT5E and promote its degradation via the ubiquitin–proteasome pathway, which could be rescued by mutation of the binding site. In summary, our findings underscore pyrimidine metabolism activity as a novel risk factor in ESCC patients and pinpoint NT5E as a novel oncogene and therapeutic target of ESCC. Moreover, we identified icaritin, a potential NT5E inhibitor, as a novel option for ESCC patients.