Metabolic Reprogramming in PDAC: The Contributions of GSTP1 to Energy Metabolism and Lipid Homeostasis

Pancreatic ductal adenocarcinoma (PDAC) is highly lethal due to its aggressive nature and limited treatment options. While glutathione S-transferase pi 1 (GSTP1) is linked to cancer development, its role in PDAC metabolism remains unclear. This study examines GSTP1 knockdown effects on energy metabolism and lipid homeostasis in PDAC cells using a multiomic approach, including transcriptomics, proteomics, and metabolomics analyses. GSTP1 knockdown revealed significantly altered expression of key metabolic genes and proteins, including reduced expression of ALDH7A1 (amino acid metabolism), CPT1A (fatty acid ?-oxidation), GLUT3 (glycolysis), and PGM1 (glycogen metabolism). Knockdown cells also displayed increased oxidative stress, with elevated reactive oxygen species (ROS) and reduced mitochondrial membrane potential and ATP levels, indicating impaired energy production. Lipidomic analysis revealed increased phospholipids, especially phosphatidylcholine, suggesting disrupted lipid metabolism. GSTP1 knockdown impairs detoxification and increases oxidative stress, affecting lipid metabolic pathways and membrane integrity. In conclusion, GSTP1 knockdown significantly affects PDAC cell energy metabolism and lipid homeostasis, highlighting potential metabolic targets for new therapies.