br Ferroptosis modulators With the

Ferroptosis modulators With the recognition that the small molecule erastin targets system xc- and thereby specifically triggers this form of death and that ferrostatin-1 prevents erastin-induced ferroptosis [2], it has become evident that ferroptosis is a druggable pathway with a number of tractable nodes that can be modulated in two ways: Ferroptosis inducers can be used to kill malignant cells, whereas ferroptosis inhibitors are applicable in diseases characterized by early cell and tissue loss [3], [5]. Ferroptosis modulators described herein are summarized in Tables 1 and 2. As aforementioned, lipoxygenase inhibitors such as zileuton, baicalein, LOXBlock-1-3, MK886, PD146176, BWA4C etc. have shown anti-ferroptotic effects, although care should be taken when using these inhibitors as most of them are either not specific or even show generalized anti-oxidant effects [3], [13]. The same holds true for U0162, a widely used MEK1/2 inhibitor initially thought to be involved in ferroptosis, until it was shown that it confers non-specific antioxidant activity [33]. Inhibition of the metabolic glutaminolysis pathway with the glutaminase inhibitor “compound 968” or amino-oxyacetic acid, a pan-transaminase inhibitor, demonstrated anti-ferroptotic effects both in fibroblasts and in isolated hearts subjected to ischemia-reperfusion injury [33]. The discovery of ACSL4 as an important downstream player of ferroptosis and its druggability with thiazolidinediones (TZD) [68], a class of compounds that was previously known to activate the peroxisome proliferator-activated gamma receptor (PPARγ) therefore used for the treatment of diabetes mellitus type 2, opens another opportunity to intervene with the ferroptosis pathway. Treatment of Cyanine 5-dCTP mg with the TZD rosiglitazone yielded the same lipidomic signature as observed in ACSL4 knockout cells and more importantly, TZDs prevented both accumulation of lipid hydroperoxides and ferroptosis induced by GPX4 inhibition/genetic disruption [6]. Besides these, phenoxazines [69] and a number of nitroxide-based compounds (untargeted or mito-targeted) including XJB-5-131, JP4-039 [70], 2,2,6,6-tetramethylpiperidin-N-oxyl (TEMPO), N-arylnitroxide, N,N-diarylnitroxide and phenoxazine-N-oxyl have been described as highly promising anti-ferroptotic agents [71]. Thereby, the nitroxides reduce peroxyl radicals with high rate constants in a catalytic manner. Regeneration of nitroxides involves two steps, first hydride transfer from the substrate to the oxoammonium ion form of nitroxide and second H-atom transfer from the resultant hydroxylamine to a peroxyl radical. An alternative approach using structure- and computation-based methods identified an allosteric site in GPX4 that allowed to discover the first GPX4 allosteric activators [72]. By increasing the enzyme activity of GPX4, these molecules suppress ferroptosis triggered by erastin and cholesterol hydroperoxides, and in addition dampen NFkB activation. None of the reported GPX4 activators presented reducing or iron chelating activity, therefore these molecules might be developed as promising cyto-protective and anti-inflammatory agents. Hence, the identification of an ever growing list of ferroptosis inducers and inhibitors as well as the unraveling of their mode of actions have greatly helped to illuminate the molecular mechanisms and the therapeutic potential of ferroptosis.
(Patho)physiological relevance Our current understanding of the relevance of ferroptotic cell death in physiologic and pathophysiologic contexts mainly stems from investigations using small molecule ferroptosis modulators and genetic mouse/cell models for key regulators of ferroptosis (Table 1, Table 2). While ferroptosis has been explored originally in the context of small molecules specifically eliciting cancer cell death by the Stockwell laboratory [2], [73], our contribution to the field began with the early recognition that the inducible deletion of the key ferroptosis regulator GPX4 in mice causes a novel non-apoptotic form of cell death in fibroblasts, neuronal cultures and in pyramidal cells of the hippocampus [24]. Later on, it was demonstrated by both groups that ferroptosis is not only limited to cancer cell death [12], but that it is also a highly relevant form of cell death in adult kidney tubular cells [13].