Meanwhile a myriad of studies using

Meanwhile a myriad of studies using tissue- and cell type-specific deletion of GPX4 have provided evidence that various tissues/cells, such as distinct neuronal cell populations including glutamatergic neurons of the forebrain [24], Purkinje cells of the cerebellum [74] and motor neurons [75], photoreceptor cells [76], kidney tubular cells [13], CD8+ T cells [41], endothelial cells [77], hepatocytes [78] and sperm cells [79] in principle can undergo ferroptosis. Just to stress here: Although a number of these studies have been performed long before the term “ferroptosis” was introduced in 2012, and instead terms other than ferroptosis such as oxytosis/non-apoptotic cell death/lipidoxytosis were used [80], they ultimately describe a similar if not the same phenomenon. In vivo studies with ferroptosis-specific inhibitors, such as liproxstatins and ferrostatins, either alone or in combination with inhibitors targeting alternative cell death pathways proved to mitigate tissue injury associated with transient ischemia/reperfusion (I/R) in liver [13] and kidney [81], oxalate crystal-induced acute kidney injury [81], intracerebral hemorrhage [82], ischemic stroke [83], or in genetic models of GPX4 deficiency in kidney [13] and keap1-nrf2 pathway [84], again highlighting the pharmacological amenability of this death pathway. It is also worth mentioning that in some tissues GPX4 deficiency can be compensated by dietary vitamin E supplementation (e.g. in endothelial cells, hepatocytes and CD8+ T cells) [77], [78], whereas other tissues are obligatory dependent on a functional GPX4/GSH system. In neurodegeneration, such as Parkinson's (PD) disease, GSH depletion, nigral iron accumulation and lipid peroxidation have been frequently described [85], [86], [87], [88], [89], [90]. Iron chelation significantly reduced neuronal damage and improved motor functions in a murine model of PD [91]. First clinical trials revealed promising results for low dose iron chelation as future therapeutic considerations for early stages of PD [91]. Hence, multicenter, parallel-group, placebo-controlled, randomized clinical trials are now recruiting PD patients to evaluate the ability of the iron chelator deferiprone to slow down disease progression in early stages of PD (ClinicalTrials.gov Identifier: NCT02655315; NCT02728843). Besides acute and chronic degenerative diseases, ferroptotic cancer cell death is the second major area which can be harnessed to combat difficult to treat cancer entities [3]. In fact, a number of small molecules ferroptosis inducers (see above) have been described in the last few years that can specifically trigger this form of cell death at least in a cellular context. Yet, in many cases their in vivo efficacy remains to be verified as some of them target nodes of the ferroptosis cascade such as system xc- and GPX4 that might be bypassed in vivo by other transporters, antioxidants etc. at least in some tumor contexts [92], or that require high amounts of the inducers [12]. As discussed above, in this context the reported tumor suppressing function of p53 by repressing expression of SLC7A11 und thus depleting cells of cysteine the might be of substantial relevance [19], [20]. On the other hand, stabilization of p53 has been demonstrated to attenuate erastin-induced ferroptotic cell death in human HT-1080 fibrosarcoma cells and primary mouse embryonic fibroblasts (but not in non-cancerous IMR-90 human fetal lung fibroblasts endogenously expressing p53) by transcriptional upregulation of target gene CDKN1A encoding for the cell-cycle arrest protein p21 [93]. Yet, inhibition of ferroptosis is presumably achieved by preserving the intracellular GSH pool rather than pure cell-cycle arrest as reported in this study [93]. P53 also inhibits dipeptidyl-peptidase-4 (DPP4) activity and DPP4 promotes lipid peroxidation and ferroptotic cell death induction in p53-deficient human colorectal cancer cells [94]. With the recent discovery that there is a clear correlation between ACSL4 expression and sensitivity to ferroptosis induction in a subset of triple negative breast cancer cells [6], new possibilities for the establishment of ferroptosis-based anticancer strategies in ACSL4 positive tumor entities may open. Remarkably, a recent study found that therapy-resistance-associated high-mesenchymal state cancer cells are highly dependent on GPX4 (unlike their non-transformed mesenchymal counterparts) and treatment with respective GPX4 inhibitors – direct and indirect ones – rendered these tumor cells highly vulnerable to this form of death [95]. This dependency seems to rely on the fatty acid composition of lipid bilayers because ACSL4 knockdown confers resistance of high-mesenchymal state cancer cells towards ferroptosis induction as previously shown for luminal-type triple negative breast cancer cells [6], [95].