TP53-dependent antitumor effects of DHODH Inhibition in nasopharyngeal carcinoma

Nucleic acid metabolism reprogramming has emerged as a common feature of cancer; however, its role in nasopharyngeal carcinoma (NPC) remains largely unexplored. This study investigated the expression patterns of nucleic acid metabolism pathways in NPC and evaluated the therapeutic potential of targeting these pathways. Via bioinformatics analysis of multiple NPC datasets, we identified significant upregulation of nucleic acid metabolism pathways in tumor tissues compared with normal nasopharyngeal epithelium. Notably, increased activity of pyrimidine biosynthesis pathways was strongly correlated with poor disease-free survival in NPC patients. Dihydroorotate dehydrogenase (DHODH), which is a rate-limiting enzyme in de novo pyrimidine synthesis, was selected as a therapeutic target. The DHODH inhibitor BAY2402234 demonstrated potent antiproliferative effects on the NPC cell lines C666-1 and NPC/HK-1 at nanomolar concentrations, with IC50 values of 4.71 nM and 3.51 nM being observed 48 h, respectively. BAY2402234 treatment significantly suppressed cell migration and invasion while inducing apoptosis. Transcriptome analysis revealed that BAY2402234 treatment led to extensive gene expression remodeling with significant activation of the TP53 signaling pathway. Functional validation experiments confirmed the essential role of TP53 in mediating the antitumor effects of BAY2402234, as siRNA-mediated TP53 knockdown substantially attenuated drug efficacy. Importantly, the low mutation rate of TP53 in NPC suggests that BAY2402234 may be particularly effective in this cancer type. These findings provide the first comprehensive evidence that nucleic acid metabolism plays a crucial role in NPC progression and that the targeting of DHODH represents a promising therapeutic strategy, particularly via TP53-dependent mechanisms.