Glutathione S‐transferase‐Pi 1 protects cells from irradiation‐induced death by inhibiting ferroptosis in pancreatic cancer

Abstract Glutathione S‐transferase‐Pi 1 (GSTP1) is an isozyme that plays a key role in detoxification and antioxidative damage. It also confers resistance to tumor therapy. However, the specific role of GSTP1 in radiotherapy resistance in pancreatic cancer (PC) is not known. In this study, we investigated how GSTP1 imparts radioresistance in PC. The findings of previous studies and this study revealed that ionizing radiation (IR) induces ferroptosis in pancreatic cancer cells, primarily by upregulating the expression of ACSL4. Our results showed that after IR, GSTP1 prolonged the survival of pancreatic cancer cells by inhibiting ferroptosis but did not affect apoptosis. The expression of GSTP1 reduced cellular ferroptosis by decreasing the levels of ACSL4 and increasing the GSH content. These changes increase the resistance of pancreatic cancer cells and xenograft tumors to IR. Our findings indicate that ferroptosis participates in irradiation‐induced cell death and that GSTP1 prevents IR‐induced death of pancreatic cancer cells by inhibiting ferroptosis.