br Introduction For decades regulated apoptosis and

Introduction For decades, regulated apoptosis and unregulated, accidental necrosis have been considered as the two sole cell death routes in multicellular organisms. With the beginning of the 21st century a paradigm shift has been witnessed by researchers in the field with the recognition that many forms of unregulated necrosis in fact do also follow certain regulated cell death routines with distinct molecular patterns and metabolic features [1]. Among these are necroptosis, pyroptosis, netosis, entosis, parthanatos, and cyclophilin D-mediated cell death, with ferroptosis being described for the first time in 2012 [2]. Ferroptosis is characterized by iron-dependent lipid peroxidation and has attracted tremendous interest owing to its unique relevance for a number of pathological conditions including tissue ischemia/reperfusion injuries (IRI), neurodegeneration and cancer [3], [4]. Cells dying by ferroptosis present a distinct bioenergetic signature, are characterized by oncosis (despite unaffected nuclei), and display aberrant mitochondrial morphology including outer membrane rupture as well as cellular disintegration, therefore lacking typical histomorphological hallmarks of apoptosis and other forms of regulated cell death. Although the final step(s) leading to ferroptotic cell death still remain(s) obscure, the occurrence of specific lipid peroxidation products in a subset of phospholipids directly precedes cellular disintegration and cell death [5]. Therefore, compounds and conditions that hamper the process of lipid peroxidation can be regarded as viable approaches to prevent ferroptosis and related disease. On the molecular level, cysteine availability, glutathione (GSH) biosynthesis and proper functioning of glutathione peroxidase 4 (GPX4) are the heart of keeping ferroptosis in check, whereas conditions that culminate in GPX4 inhibition/destabilization sensitize or even trigger ferroptotic cell death. Recently, additional players involved in polyunsaturated fatty tazemetostat (PUFA) metabolism have been added to the list of pro-ferroptotic enzymes, which are ultimately involved in shaping the cellular lipid composition [6], [7], [8]. Hence, this review is conceived to provide an overview on what is currently known about the molecular underpinnings, modulators and metabolic constraints as well as the relevance for (patho)physiological conditions in health and disease. We focus here on the mammalian system as almost everything what we have learned about ferroptosis was discovered in this system, being well aware that ferroptosis is not only limited to mammals but has also been described to occur in higher plants and in the unicellular parasite Trypanosoma brucei [9], [10], [11].
Molecular mechanisms of ferroptotic cell death Mainstay of ferroptosis is the generation of specific phospholipid hydroperoxides in the presence of catalytically active iron, which is endogenously counteracted by the system xc−/GSH/GPX4 axis [2], [12], [13]; consequently, disturbances in any of these protective compartments may result in ferroptotic cell death. The most upstream component of this axis is system xc− [14], a highly specific uptake system for cystine (i.e. the oxidized form of cysteine) and cystathionine at the exchange of glutamate at a 1:1 M ratio [15], [16] (Fig. 1). xCT (SLC7A11) light chain, which constitutes the substrate-specific subunit of system xc−, is subject to complex transcriptional regulation [17]. While xCT is positively regulated by activating transcription factor 4 (ATF4) under conditions of oxidative stress and cysteine deprivation [18], p53 was recently shown to repress xCT expression leading to cystine starvation and thus increased susceptibility to ferroptosis, thereby possibly contributing to tumor suppression [19], [20] (see also Section 5). Once taken up by system xc−, cystine is reduced to cysteine by GSH and/or thioredoxin reductase 1, which in turn is used for GSH biosynthesis [21]. While this route is the most relevant way to cope with the cells’ demand for cysteine in cell culture (where virtually all cysteine is oxidized to cystine), cysteine can also be provided to some extent by the transsulfuration pathway [22], and the neutral amino acid transporter ASC [17]. The latter being most likely the predominant way in the whole organism where the main fraction of plasma and tissue cysteine is found in its reduced form. Since cysteine is the rate-limiting substrate in GSH biosynthesis and GSH is the prevailing antioxidant in mammalian cells, conditions that impede on intracellular cysteine and consequently GSH levels impact directly GPX4 activity and thus predispose to ferroptosis.