UMP functions as an endogenous regulator of NR4A1 to control gastric cancer progression

Nucleotide metabolism reprogramming drives tumor progression, yet how tumor cells sense nucleotide levels remains unclear. Here, we identified UMP as an endogenous regulator of the orphan nuclear receptor NR4A1 in gastric cancer (GCa). Under UMP sufficiency, UMP directly binds to NR4A1, inhibiting its tumor-suppressive function and promoting GCa progression. Conversely, UMP deficiency resulting from disrupted pyrimidine biosynthesis derepresses NR4A1, which suppresses GCa cell survival and progression by both increasing NR4A1 occupancy at super-enhancers to reprogram survival-gene expression and enhancing NR4A1's pro-apoptotic activity at the mitochondria. NR4A1 loss was sufficient to rescue the effects of pyrimidine nucleotide stress on GCa cells in vitro and in vivo. NR4A1 agonists suppressed the pyrimidine salvage pathway triggered by de novo pyrimidine biosynthesis (DNPB) inhibition. Co-targeting DNPB and NR4A1 induced synergistic tumor lethality in GCa xenograft models. Together, our results establish UMP as an endogenous regulator of NR4A1 and provide an effective therapeutic strategy for GCa.