ONECUT1 is a transcriptional activator that binds specific DNA sequences to regulate gene expression, particularly in liver and pancreatic tissues 1. In hepatocytes, ONECUT1 functions as a core transcription factor controlling zonation-specific gene expression and chr15 accessibility 1. In pancreatic development, ONECUT1 is essential for pancreatic progenitor formation and endocrine differentiation, controlling transcriptional and epigenetic machinery that regulates NKX2.2/NKX6.1 expression 2. Functionally, ONECUT1 acts as a tumor suppressor in hepatoblastoma; activated β-Catenin suppresses ONECUT1 expression, leading to increased tumor cell glycolysis and hepatoblastoma formation 3. Clinically, biallelic ONECUT1 mutations cause neonatal diabetes mellitus (NDM) characterized by pancreatic hypoplasia, intrauterine growth retardation, and gallbladder abnormalities 24. Heterozygous null variants are associated with early-onset, nonautoimmune type 2 diabetes 5. Disease-causing deletions in ONECUT1 regulatory regions impair pancreatic development and cause syndromic NDM 6. Long-range enhancers controlling ONECUT1, particularly ONECUT1e-664kb, contain diabetes-associated variants that disrupt transcription factor binding 7. These findings establish ONECUT1 as critical for both monogenic (recessive and dominant) and multifactorial diabetes pathogenesis 2.