NSD3: A Promising Target for Cancer Therapy

Over the past 24 years, nuclear receptor-binding SET domain protein 3 (NSD3) has emerged as a critical regulator of cellular physiological processes. As a histone methyltransferase targeting H3K36, NSD3 catalyzes the addition of methyl groups to histone residues, a process that profoundly influences genome imprinting, gene transcription, and genome stability, thereby modulating gene expression. Amplification, mutations, and fusion events involving the NSD3 gene have been strongly linked to the pathogenesis of various cancers, highlighting its role as a key regulator of tumorigenesis. This review provides an overview of the general structure and biological functions of NSD3, followed by an analysis of NSD3's role in relation to the hallmarks of cancer as described by Hanahan and Weinberg. Targeting NSD3 has become a major focus of research, with significant efforts directed toward the development and clinical application of NSD3 inhibitors. However, challenges related to specificity and selectivity have hindered progress in this area. Despite these obstacles, the successful development and clinical advancement of other histone methyltransferase inhibitors have provided encouragement to researchers, driving the active pursuit of NSD3-targeted therapies for cancer treatment.