The dual role of ferroptosis in pancreatic cancer: A narrative review

Abstract

Pancreatic ductal adenocarcinoma is the main cause of cancer-related mortality, with a lack of effective treatments and overall survival rates far lower than other solid cancers. This clinical challenge is related to late diagnosis as well as primary or acquired resistance to therapy-induced apoptosis. Targeting nonapoptotic cell death pathways may provide alternative therapeutic strategies to overcome drug resistance. In particular, recent studies have suggested that ferroptosis, a type of iron-dependent nonapoptotic cell death, is a promising target for pancreatic ductal adenocarcinoma. Ferroptosis can be triggered by inhibiting or activating the redox or iron metabolism-related pathways, mediated by extrinsic/membrane transports (e.g., solute carrier family 7 member 11) or intrinsic/enzymes (e.g., glutathione peroxidase 4). Although the exact effector molecule remains obscure, reactive oxygen speciesinduced lipid peroxidation and subsequent plasma membrane damage appears to play a central role in mediating ferroptotic death. While treatment-induced ferroptosis is beneficial to suppress tumor growth, inflammation-related immunosuppression caused by ferroptotic damage may promote the occurrence of pancreatic ductal adenocarcinoma. In this review, we outline the latest knowledge about the regulation and function of ferroptosis in pancreatic tumorigenesis and therapy.