Regulators of system xc--glutathione-glutathione peroxidase 4 antioxidant pathway: Recent advances and challenges in targeting ferroptosis for cancer treatment.

Ferroptosis is an iron-dependent mode of cell death that is driven by phospholipid peroxides. Ferroptosis inducers (FINs) are a new paradigm in cancer treatment as several therapy-resistant cancer cells are sensitive to ferroptosis. System xc- and glutathione peroxidase 4 (GPX4) are two predominant targets of FINs. Although GPX4 inhibitors prevent the reduction of lipid peroxides, system xc- inhibitors block glutathione biosynthesis and indirectly inhibit GPX4. In this review, we provide an updated summary of GPX4 and system xc- inhibitors, as well as GPX4 degraders. We also discuss the shortcomings that impede the clinical success of these FINs for cancer treatment.