Ferroptosis inhibition by oleic acid mitigates iron-overload-induced injury
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ABSTRACT:
PROVIDER: PRJNA1020416 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26156477_1.fastq.gz | Fastqsanger.gz | |||
| SRR26156477_2.fastq.gz | Fastqsanger.gz | |||
| SRR26156478_1.fastq.gz | Fastqsanger.gz | |||
| SRR26156478_2.fastq.gz | Fastqsanger.gz | |||
| SRR26156479_1.fastq.gz | Fastqsanger.gz |
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Project description:Iron overload, characterized by accumulation of iron in tissues, induces a multiorgan toxicity whose mechanisms are not fully understood. Using cultured cell lines, Caenorhabditis elegans, and mice, we found that ferroptosis occurs in the context of iron-overload-mediated damage. Exogenous oleic acid protected against iron-overload-toxicity in cell culture and Caenorhabditis elegans by suppressing ferroptosis. In mice, oleic acid protected against FAC-induced liver lipid peroxidation and damage. Oleic acid changed the cellular lipid composition, characterized by decreased levels of polyunsaturated fatty acyl phospholipids and decreased levels of ether-linked phospholipids. The protective effect of oleic acid in cells was attenuated by GW6471 (a PPAR- antagonist), as well as in Caenorhabditis elegans lacking the nuclear hormone receptor NHR-49 (a PPAR- functional homologue). These results highlight ferroptosis as a driver of iron-overload-mediated damage, which is inhibited by oleic acid. This monounsaturated fatty acid represents a potential therapeutic approach to mitigating organ damage in iron overload individuals.
2023-10-02 | GSE243891 | GEO
Project description:Hereditary hemochromatosis and transfusional iron overload are frequent clinical conditions associated with progressive iron accumulation in parenchymal tissues leading to eventual organ failure. We have discovered a novel mechanism to reverse iron overload by pharmacological modulation of the divalent metal transporter-1 (DMT-1). DMT-1 mediates intracellular iron transport during the transferrin cycle and apical iron absorption in the duodenum. Additional functions in iron handling in the kidney and liver are less well understood. We show that the L- type calcium-channel blocker nifedipine increases DMT-1 mediated cellular iron transport 10-to 100-fold at concentrations between 1-100 uM. Mechanistically, nifedipine causes this effect by prolongation of the activity of DMT-1 to transport iron. We show that nifedipine mobilizes iron from the liver of mice with primary and secondary iron overload, and enhances urinary iron excretion. Modulation of DMT-1 function by L-type calcium-channel blockers emerges a novel pharmacological concept to treat iron overload disorders.<br> <br> In this experiment mice were subjected to dietary iron overload before being treated with nifedipine at 5 ug/g bodyweight, or mock treated with the same volume of solvent.
2007-03-01 | E-MEXP-982 | biostudies-arrayexpress
Project description:Iron overload disorders are an important factor contributing to various pathologies. However, the effects of iron overload on liver transcriptional regulation are largely unknown. To examine the effects of iron overload on liver transcriptome and chromatin accessibility, we fed mice a high-iron diet (HID) for 2 weeks. Then, livers were collected and profiled by RNA-seq and ATAC-seq.
2023-06-24 | GSE224000 | GEO
Project description:Iron overload causes the generation of reactive oxygen species, which can lead to lasting damage to the liver and other organs. We studied the effects of iron deficiency and iron overload on the hepatic transcriptional and metabolomic profile in mouse models.
2018-02-13 | GSE86236 | GEO
Project description:RATIONALE: Deferasirox may remove excess iron from the body caused by blood transfusions.
PURPOSE: This clinical trial studies deferasirox in treating iron overload caused by blood transfusions in patients with hematologic malignancies.
| 2100588 | ecrin-mdr-crc
Project description:Acute liver failure is a critical clinical issue in liver diseases, characterized by extensive hepatocyte death involving various mechanisms, including apoptosis, necroptosis, and ferroptosis. Ferroptosis, an iron-dependent form of non-apoptotic cell death marked by significant lipid peroxidation, plays a crucial role in the pathogenesis of multiple liver disorders.This cell death results in elevated levels of acute phase proteins synthesized and secreted by the liver. While previous studies indicated that the ORM2 protein does not directly influence apoptotic signaling pathways, our findings reveal that its knockout in acute liver injury models significantly worsens damage and reduces the median survival time of mice. In contrast, liver-specific overexpression of Orm2 markedly mitigates acute liver injury.We found that Orm2 exerts its protective effects by non-competitively binding to NCOA4, inhibiting ferroautophagy, and reducing iron ion accumulation, thereby decreasing ferroptosis during acute liver injury. Additionally, interference with TAX1BP1 gene expression compensates for the increased sensitivity to ferroptosis resulting from Orm2 knockdown. Importantly, ORM2 infusion therapy protects against acute damage in various organs, including the liver. Mechanistically, ORM2 in plasma enters damaged cells via endocytosis, regulating iron homeostasis and alleviating acute injury caused by ferroptosis.In summary, Orm2 is a potential protective factor against abnormal iron accumulation and ferroptosis, reducing acute organ damage. These findings suggest that acute phase proteins may play a role in cellular resistance to death during organ injury and offer a potential adjunctive therapeutic strategy for acute organ damage caused by ferroptosis.
2024-09-22 | GSE277619 | GEO
Project description:Hereditary Hemochromatosis (HH) is an autosomal recessive disorder characterized by an abnormally low expression or functional derangement of the iron regulatory hormone hepcidin. The absorption of dietary iron is disproportionate in these patients, leading to iron deposition in several tissues and consequent damage of organs including liver, heart, and pancreas. Late complications in absence of diagnosis and treatment include cirrhosis, hepatocellular carcinoma, cardiomyopathy and diabetes. Unfortunately, iron overload appears also as an acquired complication. This is the case of a variety of anemias (thalassemias, myelodysplastic syndromes, hemoglobinopathies, etc.) in which compensating mechanisms increase iron absorption. Another cause of iron overload in these patients are the repeated transfusional treatments they receive. It follows that iron overload is a common clinical problem. Therefore, we investigated the effects of iron overload on gene expression in skeletal muscle and heart using microarray technology. Genes with up-regulated expression after iron overload in both skeletal and heart muscle included angiopoietin-like 4, pyruvate dehydrogenase kinase 4 and calgranulin A and B. The expression of transferrin receptor, heat shock protein 1B and DnaJ homolog B1 were down-regulated by iron in both muscle types. Two potential hepcidin regulatory genes, hemojuvelin and neogenin, showed no clear change in expression after iron overload. Concluding, microarray analysis revealed iron-induced changes in the expression of several genes involved in the regulation of glucose and lipid metabolism, transcription and cellular stress responses. These may represent novel connections between iron overload and pathological manifestations of HH such as cardiomyopathy and diabetes. Keywords: iron induced stress response
2007-11-30 | GSE9726 | GEO
Project description:The aim of this study was to identify novel key genes and to investigate pathways involved in effect of iron-overload on atherosclerosis
2024-11-18 | GSE250599 | GEO
Project description:Iron homeostasis is essential for health; moreover, hepcidin-deficiency results in iron overload in both hereditary hemochromatosis and iron-loading anemia. Here, we identified iron modulators by functionally screening hepcidin agonists using a library of 640 FDA-approved drugs in human hepatic Huh7 cells. We validated the results in C57BL/6J mice and a mouse model of hemochromatosis (Hfe-/- mice). Our screen revealed that the anti-rheumatoid arthritis drug auranofin (AUR) potently upregulates hepcidin expression. Interestingly, we found that canonical signaling pathways that regulate iron, including the Bmp/Smad and IL-6/Jak2/Stat3 pathways, play indispensable roles in mediating AUR's effects. In addition, AUR induces IL-6 via the NF-?B pathway. In C57BL/6J mice, acute treatment with 5?mg/kg AUR activated hepatic IL-6/hepcidin signaling and decreased serum iron and transferrin saturation. Whereas chronically treating male Hfe-/- mice with 5?mg/kg AUR activated hepatic IL-6/hepcidin signaling, decreasing systemic iron overload, but less effective in females. Further analyses revealed that estrogen reduced the ability of AUR to induce IL-6/hepcidin signaling in Huh7 cells, providing a mechanistic explanation for ineffectiveness of AUR in female Hfe-/- mice. Notably, high-dose AUR (25?mg/kg) induces ferroptosis and causes lipid peroxidation through inhibition of thioredoxin reductase (TXNRD) activity. We demonstrate the ferroptosis inhibitor ferrostatin significantly protects liver toxicity induced by high-dose AUR without comprising its beneficial effect on iron metabolism. In conclusion, our findings provide compelling evidence that TXNRD is a key regulator of ferroptosis, and AUR is a novel activator of hepcidin and ferroptosis via distinct mechanisms, suggesting a promising approach for treating hemochromatosis and hepcidin-deficiency related disorders.
| S-EPMC7393508 | biostudies-literature
Project description:Cancers have unique metabolic adaptations in response to cell-intrinsic and environmental stressors, where identifying new strategies to target these adaptions is an area of active research. We previously described a dependency on a cytosolic aspartate aminotransaminase (GOT1)-dependent pathway for NADPH generation in pancreatic cancer. Here, we sought to identify metabolic dependencies following GOT1 inhibition to provide insight into the regulation of redox metabolism. Using pharmacological methods, we identified cysteine, glutathione, and lipid antioxidant function as metabolic vulnerabilities following GOT1 withdrawal. Targeting any of these pathways triggered ferroptosis, an oxidative, non-apoptotic, iron-dependent form of cell death in GOT1 knockdown cells. Mechanistically, GOT1 inhibition promoted a catabolic state and enhanced the availability of labile iron through autophagy and iron uptake. In sum, our study identifies a novel biochemical connection between GOT1, iron regulation, and ferroptosis, and suggests GOT1 plays a role in protecting PDA from metabolic stress.
2021-06-03 | GSE157830 | GEO