Lipid Metabolic Reprogramming and Chemoresistance in Pancreatic Ductal Adenocarcinoma: Insights From Lipidomics

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) exhibits profound resistance to chemotherapy that cannot be fully explained by mutational drivers alone. This review examines how lipid metabolic reprogramming contributes to cytotoxic chemotherapy resistance in PDAC and evaluates whether lipidomics and flux‐resolved metabolic analyses can identify functionally relevant therapeutic vulnerabilities. Current evidence on lipid metabolism in PDAC was reviewed, focusing on fatty acid uptake, de novo lipogenesis, desaturation, cholesterol metabolism, lipid droplet dynamics, fatty acid oxidation and ferroptosis regulation. Recent advances in lipidomic technologies, including LC–MS‐based lipidomics, single‐cell lipidomics, spatial lipid profiling and stable isotope tracing, were also evaluated for their ability to characterise metabolic states associated with cytotoxic chemotherapy resistance. PDAC cells resistant to cytotoxic chemotherapy undergo coordinated lipid metabolic rewiring involving enhanced lipid uptake and synthesis, altered fatty acid saturation balance, cholesterol‐rich membrane remodelling and increased lipid storage. These adaptations stabilise membrane architecture, sustain survival signalling, buffer oxidative stress and suppress ferroptosis. Tumour–stroma metabolic coupling further reinforces resistance through lipid exchange and metabolic interactions involving cancer‐associated fibroblasts and immune cells. Emerging lipidomic and flux‐resolved approaches reveal substantial intratumoural heterogeneity and identify lipid‐dependent survival states not captured by genomic or transcriptomic profiling alone. Chemoresistance in PDAC represents a dynamic lipid‐dependent metabolic phenotype driven by membrane remodelling and flux redistribution rather than isolated pathway activation. Integration of lipidomics with spatial and isotope‐resolved analyses may improve therapeutic stratification and support development of combination strategies targeting lipid metabolic vulnerabilities in PDAC.