Pancreatic cancer is one of the most malignant gastrointestinal tumors, and it is of great significance to explore the molecular mechanism of its progression and find new biological therapeutic targets. CIRBP is a cold-induced protein that plays a key role in many physiological and pathological processes, but its role in pancreatic cancer is still unclear. The expression of CIRBP in pancreatic cancer tissues was slightly lower than that in normal tissues, and the high expression of CIRBP was beneficial to survival. At the same time, immunohistochemical detection showed that the expression level of CIRBP in the cytoplasm of cancer tissues was significantly lower than that of adjacent tissues; survival curve analysis showed that pancreatic cancer patients with high nuclear CIRBP expression had a longer overall survival period. RIP results showed that CIRBP antibody significantly enriched p53 RNA, indicating that it could directly bind to p53. Cold treatment of pancreatic cancer cells significantly induced the expression of CIRBP, DPP4, NOX1, and FTH1 and inhibited the expression of p53 and GPX4. Cold induction enhanced the accumulation of Fe2+ in cells, promoted the generation of ROS, and inhibited the expression of GSH-Px. Therefore, cold induction promotes the process of ferroptosis by inducing the expression of CIRBP and then regulating key factors such as p53 and GPX4. In addition, cold induction significantly inhibited the proliferation of pancreatic cancer cells and induced cell apoptosis, but after the addition of ferroptosis inhibitor, cell proliferation and apoptosis did not change significantly. Therefore, CIRBP acts as a tumor suppressor gene in pancreatic cancer and induces ferroptosis through the p53/GPX4 pathway to inhibit cell growth, which may be an important target for the diagnosis and treatment of pancreatic cancer.Copyright © 2022 Hongqiang Gao et al.