Targeting PRMT5: Current Inhibitors and Emerging Strategies for Therapeutic Intervention

Epigenetic dysregulation is a hallmark of tumorigenesis, with arginine methylation—a post-translational modification—emerging as a key regulatory mechanism in cancer biology. This modification, catalyzed by protein arginine methyltransferases (PRMTs), influences critical cellular processes, including proliferation, differentiation, transcription, RNA splicing, DNA repair, and immune signaling. Among the PRMT family, PRMT5 has garnered significant attention due to its elevated expression across various solid tumors and hematological malignancies, and its strong association with poor clinical outcomes. Notably, PRMT5 exhibits a unique vulnerability in methyl-thio-adenosine phosphorylase (MTAP)-deficient cancers, making it an attractive therapeutic target. Recent advances have led to the development of several PRMT5 inhibitors with diverse binding modes, some of which have progressed into clinical trials for advanced cancers. This review provides a structural and mechanistic overview of PRMT5, summarizes current inhibition strategies, and discusses the challenges and future directions in targeting PRMT5 for cancer therapy.