Nucleotide metabolic dysregulation fuels tumor proliferation, yet its drivers in hepatocellular carcinoma (HCC) remain poorly defined. DCTPP1, a dCTP pyrophosphohydrolase linked to aggressive cancers, is overexpressed in HCC but its regulatory role is unknown. Here, integrated analyses of clinical databases and tissue microarrays revealed that high DCTPP1 expression correlates with poor prognosis in HCC patients. Functional studies demonstrated that DCTPP1 knockdown suppresses HCC proliferation, migration, and tumorigenesis in vitro and in vivo. Mechanistically, we uncovered a novel DCTPP1-MYC positive feedback loop: MYC transcriptionally activates DCTPP1, while DCTPP1 modulates MYC protein levels, potentially through the Wnt/β-catenin signaling pathway. This circuit selectively disrupts pyrimidine metabolic enzymes (CTPS1, TYMS, TK1, NME1), destabilizing the dNTP pool and accelerating HCC progression. Our work identifies DCTPP1 as an oncogenic metabolic driver in HCC, revealing a targetable vulnerability for nucleotide metabolism-directed therapy.
J et al. (Fri,) studied this question.