Major Breakthrough in Cancer Metabolism: UMP Emerges as a Novel Key Target for Precision Gastric Cancer Therapy

In the field of cancer metabolism, understanding of the functions of intermediate metabolites in nucleotide metabolism has undergone a paradigm shift. A landmark study published in Molecular Cell, led by teams led by Prof. Junjian Wang and Prof. Tao Su from Sun Yat-sen University and Prof. Hongwu Chen from the University of California, Davis, has revealed for the first time the pivotal role of uridine monophosphate (UMP) as an endogenous inhibitor of the orphan nuclear receptor NR4A1, establishing UMP as a metabolic checkpoint in gastric cancer progression.

Challenging the conventional view that UMP only serves as a precursor for RNA synthesis, this study demonstrates that UMP directly binds to the ligand-binding domain (LBD) of NR4A1, acting as an off-switch to suppress its tumor-suppressive function and thereby sustain the survival and proliferation of gastric cancer cells. These findings illuminate how tumor cells directly sense nucleotide levels via metabolites: when the de novo pyrimidine biosynthesis pathway (DNPB) is active, accumulated UMP saturates NR4A1 and blocks its anti-tumor activity.

Accordingly, the research team has proposed an innovative dual-hit strategy. Combining a DNPB inhibitor (such as BAY 2402234) to reduce UMP levels with an NR4A1 agonist (such as Csn-B) to directly activate NR4A1 elicits synthetic lethality in gastric cancer models. This approach effectively overcomes the drug-resistance bottleneck in which tumors rebound via salvage pathways when targeting metabolic pathways alone.

This work not only defines a new role for UMP as an endogenous signaling molecule but also provides a highly translationally relevant therapeutic paradigm for gastric cancer and other malignant tumors reliant on pyrimidine metabolism.

FOR DETAIL： https://doi.org/10.1016/j.molcel.2025.10.030

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