Molecular Mechanisms of Ferroptosis and Updates of Ferroptosis Studies in Cancers and Leukemia

Abstract

Ferroptosis is a mode of cell death regulated by iron-dependent lipid peroxidation. Growing evidence suggests ferroptosis induction as a novel anti-cancer modality that could potentially overcome therapy resistance in cancers. The molecular mechanisms involved in the regulation of ferroptosis are complex and highly dependent on context. Therefore, a comprehensive understanding of its execution and protection machinery in each tumor type is necessary for the implementation of this unique cell death mode to target individual cancers. Since most of the current evidence for ferroptosis regulation mechanisms is based on solid cancer studies, the knowledge of ferroptosis with regard to leukemia is largely lacking. In this review, we summarize the current understanding of ferroptosis-regulating mechanisms with respect to the metabolism of phospholipids and iron as well as major anti-oxidative pathways that protect cells from ferroptosis. We also highlight the diverse impact of p53, a master regulator of cell death and cellular metabolic processes, on the regulation of ferroptosis. Lastly, we discuss recent ferroptosis studies in leukemia and provide a future perspective for the development of promising anti-leukemia therapies implementing ferroptosis induction.

Keywords: ferroptosis; iron; leukemia; lipid peroxidation; p53; phospholipid.

Figure 1

Phospholipid metabolism and its association with ferroptosis. Fatty acid biosynthesis as well as its degradation via fatty acid oxidation or lipophagy regulates ferroptosis through modulation of phospholipids. Membrane phospholipids containing polyunsaturated fatty acids are targeted by various oxidants for peroxidation leading to ferroptosis. Abbreviations—FA, fatty acid; SA, saturated fatty acid; MUFA, mono-unsaturated fatty acid; PUFA, polyunsaturated fatty acid; PL, phospholipid; ER; endoplasmic reticulum; FA-CoA, fatty acyl-CoA, DHAP, dihydroxyacetone phosphate. The image was created with BioRender (Toronto, ON, Canada) (BioRender.com).

Figure 2

Cellular sources of labile iron pool. The level of a labile iron pool is regulated by iron import and export, storage by ferritin and its degradation (ferritinophagy), and synthesis and degradation of iron-containing proteins (heme and iron-sulfur cluster proteins). Abbreviations—ISC, iron-sulfur cluster; ETC, electron transport chain. The image was created with BioRender (BioRender.com).