Here, by using genetically defined KrasG12D-driven pancreatic cancer mouse models, human pancreatic ductal epithelial (HPDE) cell lines, human patient samples, and epidemiological data, we interrogated the role of ACSL3 signaling in PDAC progression to uncover an underlying tumorigenic mechanism with druggable attributes. This evidence concerns the gene ACSL3 and pancreatic neoplasm.