Small molecules enhance the high-efficiency generation of pancreatic ductal organoids

• Developed a novel protocol using a small molecule cocktail to generate pancreatic ductal organoids (PDOs) with high initiation efficiency and enrichment of ductal cells. • PDOs derived from Sox9-positive ductal cells exhibit remarkable stability and support long-term expansion, enabling high-throughput drug screening. • Organoids recapitulate exocrine cell composition and reflect cellular plasticity between ductal and acinar cells, providing a valuable platform for studying pancreatic diseases like PDAC. • This efficient model offers a promising tool for understanding disease mechanisms and facilitating drug development for pancreatic disorders.