Lipid signaling networks in pancreatic cancer progression and therapeutic perspectives

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, driven by aggressive biology, profound therapy resistance, and scarce treatment options. Beyond classical metabolic rewiring, recent discoveries reveal that lipid metabolism plays a central and previously underappreciated role in PDAC progression. Emerging evidence shows that fatty acids, cholesterol, lysophospholipids, sphingolipids, and oxidized lipid species actively shape oncogenic signaling, influence stromal and immune interactions, and contribute to metastasis and treatment evasion. In this review, we highlight these recent advances and discuss how lipid-driven circuits intersect with major oncogenic pathways, including KRAS effectors and phosphoinositide 3-kinase–AKT. By integrating mechanistic insights with therapeutic perspectives, we outline new opportunities to exploit lipid-based vulnerabilities in pancreatic cancer.