The Role of Orm2 in Ferroptosis Regulation and Iron Homeostasis During Acute Liver Injury and Multi-Organ Protection
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ABSTRACT:
PROVIDER: PRJNA1162917 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR30727212_1.fastq.gz | Fastqsanger.gz | |||
| SRR30727212_2.fastq.gz | Fastqsanger.gz | |||
| SRR30727213_1.fastq.gz | Fastqsanger.gz | |||
| SRR30727213_2.fastq.gz | Fastqsanger.gz | |||
| SRR30727214_1.fastq.gz | Fastqsanger.gz |
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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: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: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.
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Project description:Despite centuries of research, metastatic cancer remains incurable due to resistance against all conventional cancer therapeutics. Alternative strategies leveraging non-proliferative vulnerabilities in cancer are required to overcome cancer recurrence. Ferroptosis is an iron dependent cell death pathway that has shown promising pre-clinical activity in several contexts of therapeutic resistant cancer. However, ferroptosis sensitivity is highly variable across tissue types and cell state posing a challenge for clinical translation. We describe a convergent phenotype induced by chemotherapy where cells surviving chemotherapy have similar transcriptomic signatures and dysregulated iron homeostasis, regardless of initial cell type or chemotherapy used. Elevated labile iron levels are counteracted by NRF2 signaling that does not alleviate the amount of labile iron. Selectively inhibiting GPX4 leads to uniform susceptibility to ferroptosis in surviving cells, highlighting the common reliance on lipid peroxidation defenses. Cellular iron dysregulation is a vulnerability of chemoresistant cancer cells that can be leveraged by triggering ferroptosis
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Project description:Despite centuries of research, metastatic cancer remains incurable due to resistance against all conventional cancer therapeutics. Alternative strategies leveraging non-proliferative vulnerabilities in cancer are required to overcome cancer recurrence. Ferroptosis is an iron dependent cell death pathway that has shown promising pre-clinical activity in several contexts of therapeutic resistant cancer. However, ferroptosis sensitivity is highly variable across tissue types and cell state posing a challenge for clinical translation. We describe a convergent phenotype induced by chemotherapy where cells surviving chemotherapy have similar transcriptomic signatures and dysregulated iron homeostasis, regardless of initial cell type or chemotherapy used. Elevated labile iron levels are counteracted by NRF2 signaling that does not alleviate the amount of labile iron. Selectively inhibiting GPX4 leads to uniform susceptibility to ferroptosis in surviving cells, highlighting the common reliance on lipid peroxidation defenses. Cellular iron dysregulation is a vulnerability of chemoresistant cancer cells that can be leveraged by triggering ferroptosis
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Project description:Microvascular endothelial cells (EC) display a high degree of phenotypic and functional heterogeneity among different organs. Organ-specific EC control their tissue microenvironment by angiocrine factors in health and disease. Liver sinusoidal EC (LSEC) are uniquely differentiated to fulfil important organ-specific functions in development, under homeostatic conditions, and in regeneration and liver pathology. Recently, Bmp2 has been identified by us as an organ-specific angiokine derived from LSEC. To study angiocrine Bmp2 signaling in the liver, we conditionally deleted Bmp2 in LSEC using EC subtype-specific Stab2-Cre mice. Genetic inactivation of hepatic angiocrine Bmp2 signaling in Stab2-Cre;Bmp2fl/fl (Bmp2LSECKO) mice caused massive iron overload in the liver, and increased serum iron levels and iron deposition in several organs similar to classic hereditary hemochromatosis. Iron overload was mediated by decreased hepatic expression of hepcidin, a key regulator of iron homeostasis. Thus, angiocrine Bmp2 signaling within the hepatic vascular niche represents a constitutive pathway indispensable for iron homeostasis in vivo that is non-redundant with Bmp6. Notably, we demonstrate that organ-specific angiocrine signaling is essential not only for the homeostasis of the respective organ, but also for the homeostasis of the whole organism.
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Project description:Ex vivo normothermic machine perfusion has been proposed to protect deceased donor kidneys. However, its benefits remain ambiguous. We postulate that the use of red blood cells (RBCs) and associated secondary hemolysis may in fact cause renal injury, offsetting potential advantages. During 48-hour normothermic perfusion of seven human donor kidneys, we observed progressive hemolysis, leading to iron accumulation in perfusate, tissue, and urine. Untargeted lipidomic profiling revealed significant increases in oxidized phospholipid species in perfused kidneys, pointing towards iron-dependent cell death known as ferroptosis. Next, in twelve additional perfusions, we assessed strategies to mitigate hemolysis-driven injury. Dialysis-based free hemoglobin removal reduced lipid peroxidation, but a ferroptosis gene signature persisted. In contrast, cell-free perfusion at subnormothermia negated iron accumulation, the ferroptosis gene signature, phospholipid peroxidation, and acute kidney injury. Our findings highlight the pathological role of hemolysis and iron on the kidney, urging restraint in the clinical application of RBC-based kidney perfusion.
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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.
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