ONECUT2 is a transcription factor that functions as a master regulator in multiple cancer types, particularly driving aggressive disease phenotypes and therapeutic resistance. In prostate cancer, ONECUT2 acts as a key driver of neuroendocrine prostate cancer (NEPC) by suppressing androgen receptor signaling and promoting neuroendocrine transdifferentiation 1. It functions through direct regulation of AR target genes and the AR licensing factor FOXA1, while activating neural differentiation genes associated with lethal disease 2. ONECUT2 enhances lineage plasticity by activating multiple resistance drivers including glucocorticoid receptor and the neuroendocrine splicing factor SRRM4, promoting both adenocarcinoma and neuroendocrine variants 3. In gastric cancer, Helicobacter pylori infection upregulates ONECUT2 via NFκB, which then promotes cancer cell stemness through inhibiting PPP2R4 transcription and activating the AKT/β-catenin pathway 4. ONECUT2 also facilitates oxaliplatin resistance in gastric cancer through transcriptional activation of TFPI 5. Additionally, ONECUT2 is involved in pancreatic acinar metaplasia, identifying metaplastic cells that may contribute to pancreatic cancer development 6. The protein shows promise as a therapeutic target, with small molecule inhibitors demonstrating efficacy in preclinical models 2.