PAX4 is a paired box transcription factor essential for pancreatic β-cell development and function. As a DNA-binding transcription factor with repressor activity 1, PAX4 regulates cell-fate commitment in early endocrine progenitors toward the insulin-secreting β-cell lineage 1. PAX4 also controls enterochromaffin cell differentiation in intestinal tissue by repressing endocrine lineage commitment 2. In embryonic development, Pax4 knockout eliminates β cells while increasing glucagon-producing α cells, typically causing neonatal lethality 1. In adults, PAX4 expression is restricted to proliferative β-cell subsets; upregulation promotes β-cell survival and proliferation 1. Clinically, PAX4 mutations associate with type 2 diabetes and MODY9 3. Loss-of-function variants, including p.His192 and p.Tyr186X, impair insulin secretion and increase polyhormonal cell formation in human islets 4. However, PAX4 was statistically inconsistent with high-penetrance MODY inheritance in large population studies 5. Therapeutically, PAX4 represents a promising target: gene delivery into type 2 diabetic human islets significantly improved β-cell survival, composition, and glucose-stimulated insulin secretion 6. Ectopic PAX4 expression in α or δ cells generates functional β-like cells, potentially improving glucose regulation 1.