Ferroptosis: Death by Lipid Peroxidation

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Erastin and RSL3 were the first compounds found to induce ferroptosis, identified through high-throughput small-molecule screening.

“The first ferroptosis-inducing compounds, erastin [11] and RSL3 [12], were discovered using high-throughout screening of small molecule libraries [11, 12].”

• cites [11] Dolma S Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells Cancer Cell 2003 3 285 296 12676586 sourceNot checked yet

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• cites [12] Yang WS Stockwell BR Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells Chem Biol 2008 15 234 245 18355723 PMC2683762 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Necroptosis and ferroptosis are regulated non-apoptotic death forms that have significant roles in many biological contexts.

“Two regulated forms of non-apoptotic cell death, necroptosis and ferroptosis, have been shown recently to play significant roles in numerous biological contexts [1, 2].”

• cites [1] Linkermann A Regulated cell death and inflammation: an auto-amplification loop causes organ failure Nat Rev Immunol 2014 14 759 767 25324125 sourceNot checked yet

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• cites [2] Galluzzi L Essential versus accessory aspects of cell death: recommendations of the NCCD 2015 Cell Death Differ 2015 22 58 73 25236395 PMC4262782 sourceNot checked yet

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Ferroptosis is a non-apoptotic, peroxidation-driven regulated death process that needs abundant accessible cellular iron.

“Ferroptosis is this non-apoptotic, peroxidation-driven form of regulated cell death that requires abundant and accessible cellular iron; the existence of this ancient form of cell death was unknown and only discovered recently using a pharmacological approach [10].”

• cites [10] Dixon SJ Ferroptosis: an iron-dependent form of nonapoptotic cell death Cell 2012 149 1060 1072 22632970 PMC3367386 sourceNot checked yet

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Ferroptosis depends on iron and is genetically, biochemically, and morphologically different from apoptosis, unregulated necrosis, and necroptosis.

“This form of iron-dependent cell death is genetically, biochemically, and morphologically distinct from other cell death modalities, including apoptosis, unregulated necrosis, and necroptosis.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Ferroptosis is controlled by particular pathways and occurs in many biological settings.

“Ferroptosis is regulated by specific pathways and is involved in diverse biological contexts.”

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Erastin- and RSL3-induced death is non-apoptotic, occurring without apoptotic hallmarks and even when core apoptosis machinery is suppressed.

“The mode of cell death induced by these compounds was surprisingly found to be non-apoptotic, as cells treated with erastin and RSL3 died in the absence of apoptotic hallmarks [11, 12, 13], and in cells where the core apoptosis machinery – caspases, BAX, and BAK was suppressed [14].”

• cites [11] Dolma S Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells Cancer Cell 2003 3 285 296 12676586 sourceNot checked yet

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• cites [12] Yang WS Stockwell BR Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells Chem Biol 2008 15 234 245 18355723 PMC2683762 sourceNot checked yet

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• cites [13] Yagoda N RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels Nature 2007 447 864 868 17568748 PMC3047570 sourceNot checked yet

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• cites [14] Wolpaw AJ Modulatory profiling identifies mechanisms of small molecule-induced cell death Proc Natl Acad Sci U S A 2011 108 E771 E780 21896738 PMC3182736 sourceNot checked yet

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Ten additional compounds from the erastin/RSL3 screen induce ferroptosis; all except DPI2 inhibited GPX4 directly, while DPI2 depleted GSH like erastin.

“The screening assay in which erastin and RSL3 were identified later revealed ten additional compounds that induce ferroptosis [24, 26]. All but one compound (DPI2) inhibited GPX4 directly, similar to RSL3. In contrast, DPI2 depleted GSH, like erastin [24].”

• cites [24] Yang WS Regulation of ferroptotic cancer cell death by Gpx4 Cell 2014 156 317 331 24439385 PMC4076414 sourceNot checked yet

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• cites [26] Weiwer M Development of small-molecule probes that selectively kill cells induced to express mutant RAS Bioorg Med Chem Lett 2012 22 1822 1826 22297109 PMC3528973 sourceNot checked yet

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Rb suppresses ferroptosis in response to sorafenib, suggesting Rb status may help select ferroptosis-sensitive tumors for sorafenib.

“Recently, the retinoblastoma protein (Rb) was found to suppress ferroptosis in response to sorafenib [30], suggesting that Rb status may aid in selecting ferroptosis-sensitive tumors, at least for sorafenib.”

• cites [30] Louandre C The retinoblastoma (Rb) protein regulates ferroptosis induced by sorafenib in human hepatocellular carcinoma cells Cancer Lett 2015 356 971 977 25444922 sourceNot checked yet

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Erastin treatment blocks radiolabeled cystine import, confirming that erastin inhibits system xc−.

“Indeed, erastin treatment abolished the import of radiolabeled cystine [10], a substrate for the system xc− antiporter, confirming that erastin inhibits system xc−.”

• cites [10] Dixon SJ Ferroptosis: an iron-dependent form of nonapoptotic cell death Cell 2012 149 1060 1072 22632970 PMC3367386 sourceNot checked yet

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Glutathione depletion is enough for erastin-dependent death, because BSO also initiates ferroptosis.

“This glutathione depletion is sufficient for erastin-dependent cell death, as glutathione depletion by another reagent, buthionine sulfoxamine (BSO), also initiated ferroptosis [24].”

• cites [24] Yang WS Regulation of ferroptotic cancer cell death by Gpx4 Cell 2014 156 317 331 24439385 PMC4076414 sourceNot checked yet

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Glutamate-induced neurotoxicity is oxidative and iron-dependent, suggesting ferroptosis is involved.

“Glutamate-induced neurotoxicity is an oxidative, iron-dependent process, suggesting that ferroptosis is involved [22, 23].”

• cites [22] Tan S Oxytosis: A novel form of programmed cell death Curr Top Med Chem 2001 1 497 506 11895126 sourceNot checked yet

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• cites [23] Dixon SJ Stockwell BR The role of iron and reactive oxygen species in cell death Nat Chem Biol 2014 10 9 17 24346035 sourceNot checked yet

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Glutathione is not depleted during RSL3-induced death, supporting a different ferroptosis-initiating mechanism.

“Moreover, glutathione is not depleted during RSL3-induced cell death [24], supporting the presence of an alternative ferroptosis-initiating mechanism for RSL3.”

• cites [24] Yang WS Regulation of ferroptotic cancer cell death by Gpx4 Cell 2014 156 317 331 24439385 PMC4076414 sourceNot checked yet

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Erastin inhibits GPX4 indirectly by blocking system xc− and depleting glutathione, which explains why erastin and RSL3 share an execution mechanism despite different triggers.

“As erastin inhibits system xc− and depletes glutathione, the result is that erastin inhibits GPX4 in an indirect manner, which explains how erastin and RSL3 share a common cell death execution mechanism, but different triggering mechanisms (Figure 1).”

May combine two claims.

RSL3 inhibits GPX4 enzyme activity, since lysates from treated cells cannot reduce phosphatidylcholine hydroperoxides to alcohols.

“Cell lysates prepared from (1S, 3R)-RSL3-treated cells could not reduce phosphatidylcholine hydroperoxides into the corresponding alcohols, demonstrating that RSL3 inhibits GPX4 enzyme activity [24].”

• cites [24] Yang WS Regulation of ferroptotic cancer cell death by Gpx4 Cell 2014 156 317 331 24439385 PMC4076414 sourceNot checked yet

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FIN56 causes loss of GPX4 protein through post-translational degradation and blocks mevalonate-derived production of lipophilic antioxidants such as coenzyme Q10.

“Instead, FIN56 treatment resulted in loss of GPX4 protein through post-translational degradation, and blocked mevalonate-derived production of lipophilic antioxidants, such as coenzyme Q10 (Figure 1).”

May combine two claims.

Erastin and sulfasalazine have similar modulatory profiles, suggesting erastin may inhibit system xc− to start ferroptosis.

“In addition, modulatory profiles of erastin and sulfasalazine (SAS), an inhibitor of system xc−, were similar to each other, suggesting that erastin might act as a system xc− inhibitor to initiate ferroptosis [10].”

• cites [10] Dixon SJ Ferroptosis: an iron-dependent form of nonapoptotic cell death Cell 2012 149 1060 1072 22632970 PMC3367386 sourceNot checked yet

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RSL3 does not block cystine import, indicating it does not inhibit system xc−.

“However, RSL3 treatment does not prevent the import of radiolabeled cystine, indicating that RSL3 does not inhibit system xc− [10].”

• cites [10] Dixon SJ Ferroptosis: an iron-dependent form of nonapoptotic cell death Cell 2012 149 1060 1072 22632970 PMC3367386 sourceNot checked yet

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GPX4 is the top protein target of (1S,3R)-RSL3 in affinity pulldown proteomics, and western blotting confirmed binding.

“Analysis of mass spectrometry-based proteomic data from an affinity pulldown experiment ranked GPX4 (glutathione peroxidase 4, PHGPx) as the top protein target for (1S,3R)-RSL3 [24]; western blotting further confirmed binding between (1S,3R)-RSL3 and GPX4.”

• cites [24] Yang WS Regulation of ferroptotic cancer cell death by Gpx4 Cell 2014 156 317 331 24439385 PMC4076414 sourceNot checked yet

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CIL56- and FIN56-induced death involves lipid-ROS generation and is suppressed by vitamin E and iron chelators, confirming they are ferroptosis inducers.

“CIL56-induced and FIN56-induced cell death is accompanied by lipid-ROS generation; vitamin E and iron chelators suppressed cell death induced by these compounds [31], confirming that they are ferroptosis inducers.”

• cites [31] Shimada K Global Survey of Cell Death Mechanisms Reveals Metabolic Regulation of Ferroptosis Nat Chem Biol 2015 under review. PMC4920070 27159577 sourceNot checked yet

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The erastin/RSL3 death mode was proposed as a previously unrecognized form called ferroptosis, indicating a critical role for cellular iron.

“Taken together, the mode of cell death induced by erastin, RSL3 and related compounds was proposed to be a previously unrecognized form of cell death termed ferroptosis (ferro = “ferrous ion (Fe2+)”, ptosis = “fall”), suggesting a critical role for cellular iron in this regulated form of oxidative cell death [10].”

• cites [10] Dixon SJ Ferroptosis: an iron-dependent form of nonapoptotic cell death Cell 2012 149 1060 1072 22632970 PMC3367386 sourceNot checked yet

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GPX4 knockdown produces lipid ROS and induces ferroptosis, supporting that RSL3 acts by inhibiting GPX4.

“Moreover, knockdown of GPX4 expression generates lipid ROS and induces ferroptosis, supporting the hypothesis that (1S, 3R)-RSL3 induces ferroptosis through inhibition of GPX4 [24].”

• cites [24] Yang WS Regulation of ferroptotic cancer cell death by Gpx4 Cell 2014 156 317 331 24439385 PMC4076414 sourceNot checked yet

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Lipophilic antioxidants suppress erastin-induced death, implicating lipophilic reactive oxygen species in this process.

“Further studies [13, 17] identified lipophilic antioxidants (α-tocopherol, butylated hydroxytoluene and β-carotene) as strong suppressors of erastin-induced cell death, suggesting that reactive oxygen species (ROS), likely lipophilic in nature, were involved in this cell death process.”

• cites [13] Yagoda N RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels Nature 2007 447 864 868 17568748 PMC3047570 sourceNot checked yet

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• cites [17] Root DE Biological mechanism profiling using an annotated compound library Chem Biol 2003 10 881 892 14522058 sourceNot checked yet

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The erastin/RSL3 death phenotype is distinct from apoptosis and necroptosis.

“Therefore, the cell death phenotype induced by erastin and RSL3 is distinct from other reported modalities, including apoptosis and necroptosis.”

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Glutathione depletion lowers cellular antioxidant capacity and inhibits glutathione-dependent enzymes such as glutathione peroxidases.

“Glutathione depletion causes loss of cellular antioxidant capacity, as well as inhibition of glutathione-dependent enzymes, such as glutathione peroxidases [24, 25].”

• cites [24] Yang WS Regulation of ferroptotic cancer cell death by Gpx4 Cell 2014 156 317 331 24439385 PMC4076414 sourceNot checked yet

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• cites [25] Brigelius-Flohe R Maiorino M Glutathione peroxidases Biochim Biophys Acta 2013 1830 3289 3303 23201771 sourceNot checked yet

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In modulatory profiling, erastin and RSL3 cluster together, suggesting they share a cell death mechanism.

“Using modulatory profiling, an unbiased pharmacological and genetic profiling system in which lethal compounds are classified based on their functional profiles [14, 18], erastin and RSL3 were found to cluster together, suggesting that they share a similar cell death mechanism.”

• cites [14] Wolpaw AJ Modulatory profiling identifies mechanisms of small molecule-induced cell death Proc Natl Acad Sci U S A 2011 108 E771 E780 21896738 PMC3182736 sourceNot checked yet

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• cites [18] Wolpaw AJ Stockwell BR Multidimensional profiling in the investigation of small-molecule-induced cell death Methods Enzymol 2014 545 265 302 25065894 sourceNot checked yet

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Erastin-induced death still occurs when RIPK1/RIPK3 are knocked down or RIPK1 is inhibited, so it does not require known necroptosis components.

“Although non-apoptotic, erastin-induced cell death proceeds normally upon knockdown of RIPK1/RIPK3, or pharmacological inhibition of RIPK1 [10, 15, our unpublished data], known components of necroptosis [16].”

• cites [10] Dixon SJ Ferroptosis: an iron-dependent form of nonapoptotic cell death Cell 2012 149 1060 1072 22632970 PMC3367386 sourceNot checked yet

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• cites [15] Friedmann Angeli JP Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice Nat Cell Biol 2014 16 1180 1191 25402683 PMC4894846 sourceNot checked yet

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• cites [16] Zhou W Yuan J Necroptosis in health and diseases Semin Cell Dev Biol 2014 35 14 23 25087983 sourceNot checked yet

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In HCC cell lines, sorafenib induces non-apoptotic death that lipophilic antioxidants suppress, indicating sorafenib activates ferroptosis.

“In HCC cell lines, sorafenib was reported to induce a non-apoptotic form of cell death that was suppressed by lipophilic antioxidants [27, 28], indicating that sorafenib activates ferroptosis in HCC cell lines.”

• cites [27] Louandre C Iron-dependent cell death of hepatocellular carcinoma cells exposed to sorafenib Int J Cancer 2013 133 1732 1742 23505071 sourceNot checked yet

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• cites [28] Lachaier E Sorafenib induces ferroptosis in human cancer cell lines originating from different solid tumors Anticancer Res 2014 34 6417 6422 25368241Not checked yet

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Iron chelators block RSL3-induced death, showing that cellular iron is required.

“Moreover, iron chelators were identified as inhibitors of cell death induction, after RSL3 treatment, revealing the requirement of cellular iron [12].”

• cites [12] Yang WS Stockwell BR Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells Chem Biol 2008 15 234 245 18355723 PMC2683762 sourceNot checked yet

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GPX4 overexpression blocks death from these compounds but not other lethal agents, indicating GPX4 is a specific central regulator of ferroptotic death.

“Overexpression of GPX4 suppressed cell death induced by these compounds [24], but not other lethal agents, indicating that GPX4 is a specific and robust central regulator of ferroptotic cell death, akin to BCL-2 in apoptosis.”

• cites [24] Yang WS Regulation of ferroptotic cancer cell death by Gpx4 Cell 2014 156 317 331 24439385 PMC4076414 sourceNot checked yet

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FIN56 acts only as a ferroptosis inducer, while CIL56 also activates a non-ferroptotic mechanism at higher concentrations that depends on ACC1.

“While FIN56 acts solely as a ferroptosis inducer, CIL56 also activates a non-ferroptotic mechanism at higher concentrations and is dependent on ACC1 (acetyl-CoA carboxylase alpha) [32].”

• cites [32] Dixon SJ Human Haploid Cell Genetics Reveals Roles for Lipid Metabolism Genes in Nonapoptotic Cell Death ACS Chem Biol 2015 10 1604 1609 25965523 PMC4509420 sourceNot checked yet

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Conditional Gpx4 ablation in mouse neurons causes selective rapid motor neuron degeneration via ferroptosis and paralysis, suggesting ferroptosis may drive some motor neuron disease.

“Moreover, a recent study found that conditional ablation of Gpx4 in neurons in mice caused selective and rapid motor neuron degeneration via ferroptosis, and ultimately onset of paralysis [45]; this suggests that ferroptosis may drive some types of motor neuron disease, and its suppression is perhaps critical in motor neuron development and homeostasis.”

• cites [45] Chen L Ablation of ferroptosis inhibitor glutathione peroxidase 4 in neurons results in rapid motor neuron degeneration and paralysis J Biol Chem 2015 9 23 PMC4653669 26400084Not checked yet

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Ferrostatin-1 and its analogs protect oligodendrocytes from glutathione depletion-induced death, suggesting ferroptosis is involved in this brain injury.

“Ferrostaton-1 and its analogs also protected OLs from death by glutathione depletion, suggesting that the ferroptosis pathway is involved in this form of brain injury [57].”

• cites [57] Skouta R Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models J Am Chem Soc 2014 136 4551 4556 24592866 PMC3985476 sourceNot checked yet

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Patients with SBP2 mutations have reduced levels of most selenoproteins and a multi-symptom disorder.

“Patients with mutations in the SBP2 gene have been identified who have reduced amounts of most selenoproteins and displayed a multiple-symptom disorder [69, 70, 71, 72].”

• cites [69] Dumitrescu AM Mutations in SECISBP2 result in abnormal thyroid hormone metabolism Nat Genet 2005 37 1247 1252 16228000 sourceNot checked yet

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• cites [70] Azevedo MF Selenoprotein-related disease in a young girl caused by nonsense mutations in the SBP2 gene J Clin Endocrinol Metab 2010 95 4066 4071 20501692 sourceNot checked yet

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• cites [71] Schoenmakers E Mutations in the selenocysteine insertion sequence-binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans J Clin Invest 2010 120 4220 4235 21084748 PMC2993594 sourceNot checked yet

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• cites [72] Hamajima T Novel compound heterozygous mutations in the SBP2 gene: characteristic clinical manifestations and the implications of GH and triiodothyronine in longitudinal bone growth and maturation Eur J Endocrinol 2012 166 757 764 22247018 sourceNot checked yet

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Ferrostatin-1 is a lipid ROS scavenger that prevents erastin- and RSL3-induced ferroptosis but not staurosporine- or hydrogen peroxide-induced death.

“Ferrostatin-1 acts as a lipid ROS scavenger and prevents ferroptosis induced by erastin and RSL3, but does not suppress cell death induced by staurosporine (an apoptosis inducer) or hydrogen peroxide (an oxidative necrosis inducer) [10].”

• cites [10] Dixon SJ Ferroptosis: an iron-dependent form of nonapoptotic cell death Cell 2012 149 1060 1072 22632970 PMC3367386 sourceNot checked yet

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The transsulfuration pathway regulates ferroptosis, and erastin may be preferentially lethal to cancer cells with defective transsulfuration.

“Thus, the transsulfuration pathway is a regulator of ferroptosis; ferroptosis inducers such as erastin that block cystine uptake might be preferentially lethal to cancer cells with a defective transsulfuration pathway.”

• AssumptionRests on an assumption: The relative importance of transsulfuration versus cysteine uptake mechanisms is cell-type dependent under normal conditions.

May combine two claims.

In mice with inducible Gpx4 loss, liproxstatin-1 delays acute renal failure and extends survival compared with vehicle.

“When liprostatin-1 was administered to mice with inducible loss of Gpx4 protein, it delayed the acute renal failure caused by Gpx4 depletion, and extended survival of mice compared to a vehicle-treated group [15].”

• cites [15] Friedmann Angeli JP Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice Nat Cell Biol 2014 16 1180 1191 25402683 PMC4894846 sourceNot checked yet

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Acetaminophen induces ferroptosis in primary hepatocytes through glutathione depletion, suggesting a mechanism of drug-induced toxicity.

“Acetaminophen has been reported to induce ferroptosis in primary hepatocytes via glutathione depletion [40], suggesting this may be a mechanism of drug-induced toxicity.”

• cites [40] Lorincz T Ferroptosis is Involved in Acetaminophen Induced Cell Death Pathol Oncol Res 2015 21 1115 1121 25962350 sourceNot checked yet

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In interdigital dying tissues, apoptotic markers are present, ROS levels are elevated, and Gpx4 expression is reduced, suggesting ferroptosis activation.

“In addition to the presence of apoptotic markers in these interdigital dying tissues, ROS levels are elevated and Gpx4 expression levels are reduced, suggesting activation of ferroptosis [48].”

• cites [48] Schnabel D Expression and regulation of antioxidant enzymes in the developing limb support a function of ROS in interdigital cell death Dev Biol 2006 291 291 299 16445905 sourceNot checked yet

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Gpx4 knockout in mice causes embryonic lethality between E7.5 and E8.5, indicating Gpx4 is essential for mouse development.

“Knockout of Gpx4 in mice caused embryonic lethality between E7.5 and E8.5, indicating an essential role of Gpx4 in mouse development [42, 43].”

• cites [42] Imai H Early embryonic lethality caused by targeted disruption of the mouse PHGPx gene Biochem Biophys Res Commun 2003 305 278 286 12745070 sourceNot checked yet

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• cites [43] Yant LJ The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults Free Radic Biol Med 2003 34 496 502 12566075 sourceNot checked yet

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Kidney tissue is susceptible to ferroptosis, and ferroptosis inhibitors may help reduce kidney injury.

“These results reinforce the susceptibility of kidney tissue to ferroptosis and suggest the value of ferroptosis inhibitors to ameliorate kidney injury [59].”

• cites [59] Sancho-Martinez SM Pathophysiological role of different tubular epithelial cell death modes in acute kidney injury Clin Kidney J 2015 8 548 559 26413280 PMC4581387 sourceNot checked yet

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Mutations in endogenous RAS alleles without overexpression upregulated NRF2, which induces antioxidant genes and enhances ROS-detoxifying capacity.

“mutations in the endogenous RAS alleles (without overexpression) upregulated NRF2, a transcription factor that induces expression of antioxidant genes, enhancing the ROS-detoxifying capacity of the cells [73].”

• cites [73] DeNicola GM Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis Nature 2011 475 106 109 21734707 PMC3404470 sourceNot checked yet

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Liproxstatin-1 suppresses ferroptosis induced by erastin, RSL3, and BSO but does not rescue apoptosis or necroptosis, indicating it is a specific ferroptosis inhibitor.

“Liproxstatin-1 suppressed cell death induced by ferroptosis inducers (erastin, RSL3, and BSO), but did not rescue cells dying by apoptosis or necroptosis, indicating that liproxstatin-1 is a specific inhibitor of ferroptosis.”

May combine two claims.

SBP2 patients are highly susceptible to UV-radiation-induced oxidative damage, which is explained by deficient glutathione peroxidase synthesis.

“These patients displayed high susceptibility to UV-radiation-induced oxidative damage, which is explained by deficiency in the synthesis of glutathione peroxidases.”

May combine two claims.

HSPB1 suppresses ferroptosis by an unknown mechanism, suggesting heat shock proteins may influence ferroptosis sensitivity in some cell contexts.

“Finally, heat shock protein beta 1 (HSPB1) was reported to suppress ferroptosis through an unknown mechanism [41]; this suggests that heat shock proteins may be important in setting the sensitivity to ferroptosis in some cell contexts.”

• cites [41] Sun X HSPB1 as a novel regulator of ferroptotic cancer cell death Oncogene 2015 3 2 PMC4640181 25728673 sourceNot checked yet

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Erastin was selectively lethal in engineered cells overexpressing HRASG12V, but there was no consistent difference in erastin sensitivity between wild-type and mutated RAS cells.

“Although erastin displayed selective lethality in engineered cells overexpressing HRASG12V , there was no consistent difference in erastin sensitivity between wild-type and mutated RAS cells.”

• cites [24] Yang WS Regulation of ferroptotic cancer cell death by Gpx4 Cell 2014 156 317 331 24439385 PMC4076414 sourceNot checked yet

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SRS16-86, a third-generation ferrostatin with greater plasma and metabolic stability, protects kidney function and extends mouse survival after renal ischemia-reperfusion injury.

“SRS16–86 is a third generation ferrostatin with increased plasma and metabolic stability; in an in vivo model of renal ischemia-reperfusion injury, SRS16–86 protected kidney function and extended mouse survival after ischemia-reperfusion injury [58].”

• cites [58] Linkermann A Synchronized renal tubular cell death involves ferroptosis Proc Natl Acad Sci U S A 2014 111 16836 16841 25385600 PMC4250130 sourceNot checked yet

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In a model simulating rhabdomyolysis-induced acute kidney injury, ferrostatin-1 prevents kidney proximal tubule cell death, suggesting ferroptosis is necessary.

“Using this model, ferrostatin-1 prevented cell death in kidney proximal tubules, suggesting the necessity of ferroptosis for rhabdomyolysis-induced acute kidney injury [57].”

• cites [57] Skouta R Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models J Am Chem Soc 2014 136 4551 4556 24592866 PMC3985476 sourceNot checked yet

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Inducible Gpx4 knockout mice show that some cells and tissues, especially brain neurons, accumulate lethal lipid ROS that vitamin E can alleviate, highlighting lethal lipid peroxidation in vivo without Gpx4.

“An inducible Gpx4 knockout mouse model demonstrated that some cells and tissues, particularly neurons in the brain, accumulate lethal lipid ROS that can be alleviated by vitamin E treatment [44], highlighting the lethal nature of lipid peroxidation in vivo in the absence of Gpx4.”

• cites [44] Seiler A Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death Cell Metab 2008 8 237 248 18762024 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

SBP2 binds the SECIS element in the 3' UTR of selenoprotein mRNAs and helps insert tRNA(Sec) into the ribosomal complex at the internal UGA site.

“Selenocysteine insertion sequence binding protein 2 (SECISBP2; SBP2) binds to a stem loop RNA structure (Sec insertion sequence [SECIS] element) located in 3’-UTR region of selenoprotein mRNAs, and facilitates the incorporation of tRNA(Sec) into the ribosomal complex at the internal UGA site [68].”

• cites [68] Donovan J Copeland PR Threading the needle: getting selenocysteine into proteins Antioxid Redox Signal 2010 12 881 892 19747061 PMC2864665 sourceNot checked yet

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SLC7A11-deficient mice develop normally and are healthy.

“SLC7A11-deficient mice develop normally and are healthy [79]”

• cites [79] Sato H Redox imbalance in cystine/glutamate transporter-deficient mice J Biol Chem 2005 280 37423 37429 16144837 sourceNot checked yet

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Iron acts as a catalyst in converting peroxides into free radicals such as hydroxyl and hydroperoxyl radicals.

“Iron acts as a catalyst in converting peroxides into free radicals, such as hydroxyl and hydroperoxyl radicals.”

May combine two claims.

Artemisinin derivatives induce iron-dependent cell death, specifically ferroptosis.

“Of note, artemisinin derivatives have been reported to induce iron-dependent cell death, and specifically ferroptosis”

• cites [84] Ooko E Artemisinin derivatives induce iron-dependent cell death (ferroptosis) in tumor cells Phytomedicine 2015 22 1045 1054 26407947 sourceNot checked yet

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• cites [85] Eling N Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells Oncoscience 2015 2 517 532 26097885 PMC4468338 sourceNot checked yet

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Inhibitors of ferroptosis suppress lethality of erastin and RSL3, but do not suppress other oxidative lethal agents including H2O2, phenylarsine oxide, and rotenone.

“Second, inhibitors of ferroptosis suppress lethality of erastin and RSL3, but do not suppress other oxidative lethal agents, including H2O2, phenylarsine oxide (a general oxidizer of thiol group), and rotenone (which generates reactive oxygen species at mitochondria).”

May combine two claims.

Cu2+ and Co2+ catalyze Fenton chemistry, but do not sensitize cells to ferroptosis, whereas iron does.

“copper (Cu2+) and cobalt (Co2+) are known to catalyze Fenton chemistry, but these metals do not sensitize cells to ferroptosis, whereas iron does [10].”

• cites [10] Dixon SJ Ferroptosis: an iron-dependent form of nonapoptotic cell death Cell 2012 149 1060 1072 22632970 PMC3367386 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Iron consumption by renal cell carcinoma has been considered as a cause of iron deficiency related anemia in patients.

“In addition, iron consumption by renal cell carcinoma has been considered as the cause of iron deficiency related anemia in patients [81, 82].”

• cites [81] Kroll MH Microcytic hypochromic anemia associated with renal cell carcinoma South Med J 1984 77 635 637 6719167 sourceNot checked yet

  Not checked in the free run.

• cites [82] Dowd AA Renal cell carcinoma as a cause of iron deficiency anemia African Journal of Urology 2014 20 25 27 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

HO-1 is induced upon erastin treatment and accelerates erastin-induced ferroptosis.

“the iron-containing heme oxygenase-1 (HO-1) was reported to be induced upon erastin treatment and to accelerate erastin-induced ferroptosis[87]”

• cites [87] Kwon MY Heme oxygenase-1 accelerates erastin-induced ferroptotic cell death Oncotarget 2015 6 24393 24403 26405158 PMC4695193 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Ferrostatins inhibit ferroptosis in diverse contexts.

“as well as the use of ferrostatins to inhibit ferroptosis in diverse contexts.”

May combine two claims.

Free radicals generated by Fenton chemistry are highly reactive to biomolecules and induce nonspecific, massive oxidative damage to cells.

“Moreover, the free radicals generated by Fenton chemistry are highly reactive to biomolecules and induce nonspecific, massive oxidative damage to cells”