Regulatory pathways and drugs associated with ferroptosis in tumors

Abstract

Ferroptosis is a type of cell death that depends on iron and reactive oxygen species (ROS). The accumulation of iron and lipid peroxidation primarily initiates oxidative membrane damage during ferroptosis. The core molecular mechanism of ferroptosis includes the regulation of oxidation and the balance between damage and antioxidant defense. Tumor cells usually contain a large amount of H2O2, and ferrous/iron ions will react with excessive H2O2 in cells to produce hydroxyl radicals and induce ferroptosis in tumor cells. Here, we reviewed the latest studies on the regulation of ferroptosis in tumor cells and introduced the tumor-related signaling pathways of ferroptosis. We paid particular attention to the role of noncoding RNA, nanomaterials, the role of drugs, and targeted treatment using ferroptosis drugs for mediating the ferroptosis process in tumor cells. Finally, we discussed the currently unresolved problems and future research directions for ferroptosis in tumor cells and the prospects of this emerging field. Therefore, we have attempted to provide a reference for further understanding of the pathogenesis of ferroptosis and proposed new targets for cancer treatment.

Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs)

“…A major antioxidant pathway that prevents ferroptosis is the SLC7A11/GSH/GPX4 axis [ 20 ]. In this study, no modification in SLC7A11 mRNA or protein expression was detected, despite a significant decrease in the GSH content.…”

“…In conclusion, our in vitro data establish a role of ferroptosis induction in GISTs. Given the potential of targeting ferroptosis in various types of cancers [ 20 ], it is tempting to speculate that, also in GISTs, ferroptosis could be considered as a mechanism subjected to therapeutic targeting. We provide evidence that the pharmacological inhibition of YAP by VP induces ferroptosis in two human GIST cell lines, while CA3 induces ferroptosis independently of YAP inhibition.…”

“…Ferroptosis is a non-apoptotic iron-dependent form of cell death characterized by an accumulation of lipid peroxidation that leads to membrane damage [ 17 , 18 , 19 ]. Ferroptosis is the result of an imbalance between oxidative damage and antioxidant defense [ 19 , 20 ]. Oxidative damage is either caused by an accumulation of radical oxygen species (ROS), mainly produced by the Fenton reaction which involves free ferrous iron and H 2 O 2 , or lipid peroxidation mediated by iron-containing lipoxygenases (LOX) [ 18 , 19 , 21 ].…”

“…SLC7A11 is one of the two subunits of the cystine–glutamate antiporter system X c − that imports extracellular cystine into the cytoplasm, where it is used in the biosynthesis of GSH, the cofactor of the antioxidant enzyme GPX4. This later reduces hydroperoxide lipids and thus prevents ferroptosis [ 18 , 19 , 20 ].…”

Targeting NRF2 Sensitizes Esophageal Adenocarcinoma Cells to Cisplatin through Induction of Ferroptosis and Apoptosis

“…The occurrence of ferroptosis was largely dependent on NRF2 inhibition by Brusatol. Ferroptosis, a form of cell death, is recognized as an important molecular mechanism that can effectively kill cancer cells [ 56 , 57 ]. Glutathione peroxidase 4 (GPX4) is a key inhibitor of ferroptosis, and its downregulation in response to therapy coincides with the occurrence of ferroptosis [ 58 , 59 ].…”