RNA-sequencing and Exome-sequencing analysis of ferroptosis-resistant 786-O GPX4-null carcinoma cells following in vivo selection
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PROVIDER: PRJNA623805 | ENA |
REPOSITORIES: ENA
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Project description:We have used in vivo selection to isolate GPX4 knockout 786-O cells that have evaded ferroptosis in vivo in mouse xenograft experiments. RNA-seq and Exome-seq profiling were performed to characterize the mechanisms underlying ferroptosis evasion in these in vivo-derived ferroptosis resistant cells.
2020-09-16 | GSE148297 | GEO
Project description:Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial distribution of renal GPX4-mediated ferroptosis and the molecular events causing GPX4 reduction during ischemia-reperfusion (I/R) remain largely unknown. Using spatial transcriptomics, we identify that GPX4 is situated at the interface of the inner cortex and outer medulla, a hyperactive ferroptosis site post-I/R injury. We show that OTU deubiquitinase 5 (OTUD5) is a GPX4-binding protein that confers ferroptosis resistance by stabilizing GPX4. During I/R, ferroptosis is induced by mTORC1-mediated autophagy, causing OTUD5 degradation and subsequent GPX4 decay. Functionally, OTUD5 deletion intensifies renal tubular cell ferroptosis and exacerbates acute kidney injury, while AAV-mediated OTUD5 delivery mitigates ferroptosis and promotes renal function recovery from I/R injury. In this work, our study highlights a new autophagy-dependent ferroptosis module: hypoxia/ischemia-induced OTUD5 autophagy triggers GPX4 degradation, offering a potential therapeutic avenue for I/R-related kidney diseases.
2023-11-29 | GSE244330 | GEO
Project description:Ferroptosis is a recently identified program of regulated cell death, defined by excessive accumulation of hydroperoxy-arachidonoyl (C20:4)- or adrenoyl (C22:4)- phosphatidyl-ethanolamine (OOH-PE). The selenium-dependent glutathione peroxidase 4 (GPX4) inhibits ferroptosis, converting unstable ferroptotic lipid hydroperoxides to non-toxic lipid alcohols. The effect of GPX4 ablation is divergent among cells and tissues, suggesting that additional regulators may guard trophoblasts against ferroptosis. While placental oxidative stress and lipotoxicity are hallmarks of placental dysfunction, the possible role of ferroptosis in placental function has not been hitherto investigated. Here we found that placental dysfunction is associated with ferroptosis, and that inhibition of GPX4 causes trophoblast injury and ferroptosis in vitro and in vivo during mouse pregnancy. Importantly, we uncover a role for the phospholipase PLA2G6 (PNPLA9, iPLA2beta), known to metabolizes OOH-PE to lyso-PE and oxidized fatty acid, in mitigating ferroptosis induced by GPX4 inhibition in vitro or by hypoxia-reoxygenation injury in vivo. Together, we identified ferroptosis in the human and mouse placenta, and established a novel role for PLA2G6 in attenuating trophoblastic ferroptosis. Our data provide mechanistic insights to the ill-defined entity of placental lipotoxicity, and may inspire new therapeutic strategies that target PLA2G6 as a means to modulate ferroptosis in placental and non-placental tissue.
2020-09-27 | GSE147625 | GEO
Project description:Clear-cell carcinomas (CCCs) are a histological group of highly aggressive malignancies commonly originating in the kidney and ovary. CCC tumors are distinguished by aberrant lipid and glycogen accumulation and are inherently refractory to a broad range of anti-cancer therapies. In the study associated with this dataset, we identified an intrinsic vulnerability to ferroptosis associated with the unique metabolic state in CCC cells. However, the mediators of this sensitivity to ferroptosis are unknown. Here we perform a genome-wide CRISPR screen to identify genes that mediate the sensitivity to ML210, a selective inhibitor of glutathione peroxidase 4 (GPX4) and a potent inducer of ferroptotic cell death in 786-O, a clear-cell renal cell carcinoma cell line.
2019-03-04 | GSE126696 | GEO
Project description:Analysis of ferroptosis markers from cells isolated from neuroblastoma orthotopic xenograft mouse model. We combine simultaneous inhibition of cysteine uptake and transsulfuration in xenograft model using SK-N-DZ cell line. We treated the mice with IKE and PPG together with genetic targeting of GPX4 activity. At the end of the treatment, transcriptional profiling of residual small tumors revealed induction of ferroptosis markers after combined inhibition of cystine uptake/cysteine synthesis and GPX4 as compared to tumors treated with vehicle control.
2022-01-05 | GSE192976 | GEO
Project description:Background: Intestinal failure-associated liver disease (IFALD) is a common complication of long-term parenteral nutrition (PN) that is associated with significant morbidity and mortality. Ferroptosis, as an iron-dependent regulated cell death, has been shown to play an important role in the development of several liver diseases. This study focuses on investigating whether the ferroptosis phenomenon is present in TPN-induced IFALD and further exploring the potential regulatory mechanisms. Methods: Ferroptosis hallmarkers were measured in children with short bowel syndrome (SBS) who had long-term PN use and caused IFALD. Sprague-Dawley (SD) rats were used to establish a rat model of IFALD with a concomitant ferroptosis inhibition intervention using liproxstain-1. The mir-431 lineage was identified as a potential upstream regulatory mir-RNA by mir-RNA sequencing. HepG2 and 293T cell line was used to demonstrate that mir-431 regulates ferroptosis through the GPX4 pathway at the cellular level in vitro. Results: Ferroptosis is upregulated in liver of children with IFALD. Liproxstain-1 downregulates ferroptosis in a rat model of IFALD and attenuates hepatic steatosis through the lipid metabolism pathway. In vitro HepG2 and 293T cell experiments reveal that mir-431 affects ferroptosis by regulating GPX4 protein. Conclusions: Ferroptosis plays an important role in the development of IFALD. Liproxstain-1 inhibits ferroptosis and attenuates hepatic steatosis in a rat model of IFALD through the lipid metabolism pathway. Mir-431 negatively regulates GPX4 protein-induced ferroptosis.
2024-01-01 | GSE222802 | GEO
Project description:Background: Intestinal failure-associated liver disease (IFALD) is a common complication of long-term parenteral nutrition (PN) that is associated with significant morbidity and mortality. Ferroptosis, as an iron-dependent regulated cell death, has been shown to play an important role in the development of several liver diseases. This study focuses on investigating whether the ferroptosis phenomenon is present in TPN-induced IFALD and further exploring the potential regulatory mechanisms. Methods: Ferroptosis hallmarkers were measured in children with short bowel syndrome (SBS) who had long-term PN use and caused IFALD. Sprague-Dawley (SD) rats were used to establish a rat model of IFALD with a concomitant ferroptosis inhibition intervention using liproxstain-1. The mir-431 lineage was identified as a potential upstream regulatory mir-RNA by mir-RNA sequencing. HepG2 and 293T cell line was used to demonstrate that mir-431 regulates ferroptosis through the GPX4 pathway at the cellular level in vitro. Results: Ferroptosis is upregulated in liver of children with IFALD. Liproxstain-1 downregulates ferroptosis in a rat model of IFALD and attenuates hepatic steatosis through the lipid metabolism pathway. In vitro HepG2 and 293T cell experiments reveal that mir-431 affects ferroptosis by regulating GPX4 protein. Conclusions: Ferroptosis plays an important role in the development of IFALD. Liproxstain-1 inhibits ferroptosis and attenuates hepatic steatosis in a rat model of IFALD through the lipid metabolism pathway. Mir-431 negatively regulates GPX4 protein-induced ferroptosis.
2024-01-01 | GSE223895 | GEO
Project description:Purpose: Identification of Gpx4-dependent genes in resting and activated Treg cells Methods: RNA was purified from resting of stimulated (aCD3-CD38 for 4 h) splenic Treg cells sorted from WT or Foxp3CreGpx4fl/fl mice Conclusions: Gpx4 prevents lipid peroxidation and ferroptosis of activated Treg cells..
2021-10-31 | GSE160338 | GEO
Project description:Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate this form of cell death are needed. We applied two independent approaches, a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines to uncover acyl-CoA synthetase long-chain family member 4 (Acsl4) as an essential component for ferroptosis execution.
2017-06-01 | GSE86384 | GEO
Project description:Erastin is a small molecular compound which inhibits the system Xc- and prevents the import of cystine, reducing glutathione (GSH) biosynthesis and glutathione peroxidase 4 (GPX4) activity, and finally inducing cell death via ferroptosis. To establish a model of Erastin induced ferroptosis in glioma cells, U87 cells were treated of Erastin (10 μM, 72 h). Combination analysis of HiChIP, ChIP-seq and RNA-seq data suggests that change of chromatin loops mediated by 3D chromatin structure regulate gene expressions in glioma ferroptosis. Genes that regulated by 3D chromatin structure include genes that were reported function in ferroptosis like MDM2 and TXRND1. We propose a new regulatory mechanism governing glioma cell ferroptosis by 3D chromatin structure.
2023-10-23 | GSE236253 | GEO