Narrative review on fructose metabolism in pancreatic ductal adenocarcinoma stress tolerance

While previous research has established fructose as an alternative carbon source for tumors and implicated it in the metabolic reprogramming of pancreatic cancer, a comprehensive understanding of its coordinated regulation through exogenous uptake and endogenous synthesis, and its coupling with stress adaptation mechanisms like stress granules (SGs) to form an “adaptive survival axis,” remains incomplete. This study employed a mechanism-oriented narrative review approach to integrate existing evidence on the regulatory mechanisms of fructose metabolism and stress response signaling in pancreatic ductal adenocarcinoma (PDAC), based on literature identified from PubMed, Web of Science, and CNKI databases. Our findings indicate that fructose is taken up via GLUT5 and endogenously synthesized through the Pentose Phosphate Pathway (PPP). It subsequently modulates redox homeostasis and autophagy via the pentose phosphate pathway, lipid synthesis, and the AMPK/mTORC1 signaling pathway. Concurrently, fructose induces eIF2α phosphorylation and the phase separation of RNA-binding proteins to form SGs. These SGs act as a metabolic-signaling coupling platform, synergizing with the KRAS-NUPR1 pathway to enhance tumor stress tolerance. By integrating these pathways, this study innovatively proposes a framework of the “fructose metabolism-driven adaptive survival axis” in PDAC, positing fructose metabolism as a critical adaptive survival axis that combines metabolic reprogramming with stress tolerance. This provides a theoretical basis for developing synthetic lethality strategies targeting “fructose uptake/metabolic enzymes + blockade of SG formation” and precision nutritional interventions. Consequently, this research not only advances our understanding of pancreatic cancer metabolism but also reveals therapeutic opportunities involving metabolic targeting, stress granule modulation, and precision nutritional intervention.