Ferroptosis Resistance in Cancer: An Emerging Crisis of New Hope

Ferroptosis, a new mode of nonapoptotic cell death, is increasingly recognized as a new hope in overcoming resistance to chemotherapy in cancer. Both canonical and noncanonical pathways can trigger ferroptosis execution via an iron-dependent lethal lipid peroxidation manner. However, growing evidence has shown that some cancer cells can survive ferroptotic stress through metabolic remodeling as regards iron metabolism, anti-oxidative systems, and lipid metabolism. In addition to the well-known roles of the XC−/glutathione/glutathione peroxidase 4 (XC−/GSH/GPX4) axis in blocking ferroptosis, several recently identified pathways, including the Mevalonate-ferroptosis suppressor protein 1 (MVA-FSP1) axis, the GTP cyclohydrolase 1-Tetrahydrobiopterin (GCH1-BH4) axis, the peroxisome-ether-phospholipid axis, the acyl-CoA synthetase long-chain family member 3-monounsaturated fatty acids (ACSL3-MUFA) axis, and the Liver kinase B1-AMP-activated protein kinase (LKB1-AMPK) axis, can negatively regulate susceptibility to ferroptosis. Prominin-2, a newly identified ferroptosis-modulating protein, also drives cancer cells to escape from ferroptosis induction. These findings collectively led to major challenges and opportunities in the development of novel therapies that target the ferroptosis resistance of cancer cells. Significance Ferroptosis is a lethal consequence of accumulated lipid peroxidation catalyzed by ferrous iron and oxygen. This unique cell death process appears to involve many diseases, such as neurodegeneration, ischemia/reperfusion injury, kidney disease, and a druggable target in therapy-resistant cancers. There is great expectation of being able to exploit ferroptosis for the treatment of as yet incurable diseases. However, the state of ferroptosis susceptibility is linked to various regulation pathways. This perspective aims to integrate the current understanding of signaling mechanisms for ferroptotic defenses and facilitates movement toward novel cancer therapeutic strategies