Targeting vulnerability in tumor therapy: Dihydroorotate dehydrogenase

Dihydroorotate dehydrogenase (DHODH) is a key enzyme in the de novo pyrimidine biosynthetic pathway and a recognized therapeutic target in various diseases. In oncology research, DHODH has gained increasing importance and become a hot target for various tumor therapy studies. This review highlights three key points: (1) DHODH enables its diverse biological functions through its unique structural features and dominates the regulation of tumor metabolism and cell fate; (2) DHODH activates oncogenic signals, drives metastatic adaptation, and remodels drug resistance networks in tumors, making it a metabolic-signaling dual hub; and (3) DHODH inhibitors have shown significant efficacy in preclinical models of various tumors but face multiple challenges in clinical trials, including drug-related limitations and external constraints. Given these challenges, future research should explore DHODH inhibitors as a foundation for overcoming technological and translational barriers while establishing a systematic framework for the clinical application of DHODH-targeted tumor therapies.