Gemcitabine is widely used in the treatment of pancreatic ductal adenocarcinoma (PDAC), but the development of chemoresistance poses a significant challenge to achieving long-term disease-free survival in PDAC patients.1 Resistance to gemcitabine may arise from various cellular and molecular changes in metabolism, tumor microenvironment, and DNA damage repair efficiency.2 Despite existing knowledge, large-scale molecular mechanisms underlying gemcitabine resistance remain unclear. Understanding these mechanisms could lead to more effective treatment strategies for this highly aggressive disease.