Progress in Understanding Ferroptosis and Challenges in Its Targeting for Therapeutic Benefit

Abstract

Ferroptosis is an iron-dependent cell-death modality driven by oxidative phospholipid damage. In contrast to apoptosis, which enables organisms to eliminate targeted cells purposefully at specific times, ferroptosis appears to be a vulnerability of cells that otherwise use high levels of polyunsaturated lipids to their advantage. Cells in this high polyunsaturated lipid state generally have safeguards that mitigate ferroptotic risk. Since its recognition, ferroptosis has been implicated in degenerative diseases in tissues including kidney and brain, and is a targetable vulnerability in multiple cancers-each likely characterized by the high polyunsaturated lipid state with insufficient or overwhelmed ferroptotic safeguards. In this Perspective, we present progress toward defining the essential roles and key mediators of lipid peroxidation and ferroptosis in disease contexts. Moreover, we discuss gaps in our understanding of ferroptosis and list key challenges that have thus far limited the full potential of targeting ferroptosis for improving human health.

Figure 1.. Chemical basis of lipid peroxidation and ferroptosis.

Abbreviations: GPX4, glutathione peroxidase 4; L-H, symbol for polyunsaturated lipids; Vit. E, vitamin E; Lip-1, liproxstatin-1; Fer-1, ferrostatin-1; IKE, imidazole ketone erastin; DFO, deferoxamine; BSO, L-Buthionine-(S,R)-Sulfoximine; GSH, reduced glutathione.

Figure 2.. Mechanisms mediating ferroptosis sensitivity and resistance in cells.

Red: genes, metabolites, and methods that increase cellular sensitivity to ferroptosis. Green, genes, metabolites, and methods that decrease cellular sensitivity to ferroptosis. Abbreviations: PUFA, polyunsaturated fatty acids; MUFA, monounsaturated fatty acids; PROM2, Prominin2; AIFM2/FSP1, apoptosis inducing factor, mitochondrion-associated, 2 (recently renamed as ferroptosis suppressor protein 1); HILPDA, hypoxia-induced, lipid droplet associated protein; HIF-2ɑ, hypoxia-inducible factor 2ɑ; ACSL4, acyl-CoA synthetase, long-chain family member 4; LPCAT3, lysophosphatidylcholine acyltransferase 3; ESCRT, endosomal sorting complexes required for transport machinery; iNOS, inducible nitric oxide synthase.