Islamic Azad University, Science and Research Branch

In KRAS-mutant and KRAS wild-type pancreatic ductal adenocarcinoma cells (PANC-1, BxPC-3) and a PANC-1 subcutaneous xenograft model, this study shows that the natural polyphenol ellagic acid (EA) combined with the GPX4 inhibitor RSL3 synergistically reduces cell viability and suppresses tumor growth by activating p38 MAPK and upregulating Keap1 to inhibit the Nrf2/HO-1 antioxidant axis, amplifying ferroptotic hallmarks such as iron accumulation, lipid peroxidation, and GPX4 downregulation, with Fer-1 rescuing viability while apoptosis, necroptosis, and autophagy inhibitors do not.

In KRAS-mutant and KRAS wild-type pancreatic ductal adenocarcinoma cells (PANC-1, BxPC-3) and a PANC-1 subcutaneous xenograft model, this study shows that the natural polyphenol ellagic acid (EA) combined with the GPX4 inhibitor RSL3 synergistically reduces cell viability and suppresses tumor growth by activating p38 MAPK and upregulating Keap1 to inhibit the Nrf2/HO-1 antioxidant axis, amplifying ferroptotic hallmarks such as iron accumulation, lipid peroxidation, and GPX4 downregulation, with Fer-1 rescuing viability while apoptosis, necroptosis, and autophagy inhibitors do not.