Ribonucleotide reductases in cancer: Mechanisms, clinical progress, and prospects

Ribonucleotide reductase (RNR) catalyzes the rate limiting conversion of ribonucleotides to deoxyribonucleotides (dNTPs), essential for DNA synthesis and repair. Aberrant RNR activity in cancer drives genomic instability, promoting tumor proliferation, metastasis and resistance to therapeutic interventions. Consequently, RNR have emerged as promising therapeutic targets in oncology. Clinically approved RNR-targeting agents, such as nucleoside analogs (e.g., gemcitabine) and radical scavengers (e.g., hydroxyurea), are limited by intrinsic and acquired resistance mechanisms. Recent advances have identified novel RNR inhibition strategies, such as RNA interference, cyclin-dependent kinase inhibitors (e.g., GW8510), and subunit and proteolysis-targeting agents (e.g., DHS analogs). This review comprehensively examines the structural architecture and catalytic mechanisms of RNR, alongside their regulation at transcriptional, translational, and post-translational levels. We systematically analyze RNR dysregulation in malignancies, elucidating oncogenic mechanisms and the therapeutic constraints of conventional inhibitors. Finally, we highlight emerging pharmacological agents targeting RNR pathways, emphasizing their translational potential in contemporary oncology research.