A Nature report showed that inhibiting the epigenetic regulator NSD2 can reverse resistance in neuroendocrine prostate cancer (a treatment‑resistant CRPC subtype), restoring sensitivity to androgen receptor blockade such as enzalutamide. The study combined genetic models, epigenomic mapping and drug-response assays to define NSD2 as a therapeutic vulnerability. Authors demonstrated that NSD2 drives chromatin changes supporting lineage plasticity and drug resistance; targeting NSD2 reprogrammed tumor epigenetics and reduced growth in preclinical models. The paper outlines NSD2 inhibitors and genetic suppression as potential strategies to resensitize tumors. Translational work must deliver selective NSD2 inhibitors with brain/tumor penetration and tolerable safety profiles, and define predictive biomarkers to identify patients likely to benefit from NSD2‑directed combination therapies.