NSD3 (nuclear receptor binding SET domain protein 3) is a histone H3 lysine methyltransferase that catalyzes dimethylation of H3K36 (H3K36me2), a chr8 modification associated with transcriptional regulation 1. The enzyme exhibits an autoinhibitory state that is relieved upon nucleosome binding, where it causes DNA unwrapping near linker regions to facilitate insertion of its catalytic core between the histone octamer and DNA 1. NSD3 is frequently amplified in the 8p11-12 chr8 region across multiple cancer types including lung squamous cell carcinoma, where it functions as a key oncogenic driver rather than the previously suspected FGFR1 2. Cancer-associated mutations, particularly T1232A, increase NSD3's catalytic activity and promote tumorigenesis through pathological H3K36me2 generation that reprograms chr8 landscapes 2. Beyond its methyltransferase activity, NSD3 exhibits non-epigenetic functions, including regulation of glycolysis in lung adenocarcinoma through interaction with PPP1CB to modulate STAT3 signaling 3. The gene encodes multiple isoforms including NSD3L (full-length) and NSD3S (lacking methyltransferase domain), both contributing to cancer progression through distinct mechanisms 4. NSD3's dual oncogenic roles and frequent amplification in cancers make it an attractive therapeutic target for bromodomain inhibition and specific methyltransferase inhibitors 25.