Cracking PRMT5: Mechanistic insights, clinical advances, and AI-driven strategies

Protein arginine methyltransferase 5 (PRMT5) is a type II methyltransferase that catalyzes symmetric arginine dimethylation on histone and non-histone proteins, thereby modulating transcription, RNA splicing, and diverse signaling pathways. Dysregulated PRMT5 activity contributes to tumorigenesis and multiple pathological conditions, positioning it as a high-priority therapeutic target with strong translational relevance. Current inhibitor strategies encompass S-adenosylmethionine (SAM)-competitive agents, substrate-competitive and substrate-dependent modulators, dual-binding and methylthioadenosine (MTA)-cooperative inhibitors, PROTAC-based degraders, repurposed FDA-approved drugs, and rational combination regimens designed to improve efficacy or overcome resistance. These approaches differ in mechanism of action, tumor specificity, and toxicity profiles. This review highlights their mechanistic underpinnings, clinical development, and inherent limitations, while also examining the potential application of PRMT5 inhibitors in non-oncologic indications, including ocular and cardiovascular diseases. Finally, it explores the role of biomedical informatics and artificial intelligence (AI) in drug repurposing and outlines future directions for advancing PRMT5-targeted therapeutics.