Abstract Ferroptosis has emerged as a potential therapeutic target in cancer. This study shows the critical role of AGR2 in ferroptosis suppression across pancreatic cancer cell lines and in vivo models. Notably, human pancreatic cancer cells exhibit dose-dependent AGR2 upregulation upon exposure to ferroptosis inducers. Genetic ablation of AGR2 significantly sensitizes cells to ferroptosis through a p53-mediated mechanism, while p53 knockdown effectively rescues ferroptosis resistance.