Targeting GPX4-mediated ferroptosis alleviates liver injury in a rat model of intestinal failure-associated liver disease
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ABSTRACT:
PROVIDER: PRJNA928757 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR23255578.fastq.gz | Fastqsanger.gz | |||
| SRR23255579.fastq.gz | Fastqsanger.gz | |||
| SRR23255580.fastq.gz | Fastqsanger.gz | |||
| SRR23255581.fastq.gz | Fastqsanger.gz | |||
| SRR23255582.fastq.gz | Fastqsanger.gz |
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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: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: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:Invariant natural killer T (iNKT) cells are a group of innate like T cells that plays important roles in immune homeostasis and activation. We found that iNKT cells, compared to CD4+ T cells, have significantly higher levels of lipid peroxidation in both mice and humans. Proteomic analysis also demonstrated that iNKT cells express higher levels of Glutathione peroxidase 4 (Gpx4), a major antioxidant enzyme that reduces lipid peroxidation and prevents ferroptosis. T cell specific deletion of Gpx4 reduces iNKT cell population, most prominently the IFNg producing NKT1 subset. RNAseq analysis revealed IFNg signaling, cell cycle regulation, as well as mitochondrial function are perturbed by Gpx4 deletion in iNKT cells. Consistently, we detected impaired cytokine production, elevated cell proliferation and cell death, and accumulation of lipid peroxides and mitochondrial ROS in Gpx4 KO iNKT cells. Ferroptosis inhibitor, iron chelator, vitamin E and vitamin K2 can prevent ferroptosis induced by Gpx4 deficiency in iNKT cells and ameliorate the impaired function of iNKT cells due to Gpx4 inhibition. Lastly, vitamin E rescued iNKT cell population in Gpx4 KO mice. Altogether, our findings reveal the critical role of Gpx4 in regulating iNKT cell homeostasis and function, through controlling lipid peroxidation and ferroptosis.
2024-08-20 | GSE270485 | GEO
Project description:Numerous neurological diseases involve neuroinflammation, a process in which immune cells, particularly microglia, contribute to neuronal death. Ferroptosis, a recently identified form of regulated cell death, is implicated in various diseases characterized by neuronal injury. Nicotinamide mononucleotide (NMN), a potent NAD+ precursor supplement, has been found to inhibit neuroinflammation and ferroptosis. However, the mechanisms of NMN in both ferroptosis and neuroinflammation remains unclear. The present study aimed to investigate the impact of NMN on neuroinflammation and the susceptibility of microglia to ferroptosis. Ferroptosis markers in microglia exposed to lipopolysaccharide (LPS) were analyzed using CCK8, flow cytometry, ELISA, and RT-qPCR. The effects of NMN on LPS-induced ferroptosis in microglia were evaluated through flow cytometry, western blotting, and immunofluorescence staining. RT-qPCR analysis assessed the inflammatory cytokine production of microglia subjected to ferrostatin-1-regulated ferroptosis. RNA sequencing elucidated the underlying mechanisms of NMN-associated microglia ferroptosis under LPS induction. In BV2 microglia, an inhibitor of Glutathione Peroxidase 4(GPX4), RSL3, was employed to suppress GPX4 expression. Intracerebroventricular injection of LPS was performed to evaluate neuroinflammation and microglia activation in vivo. LPS treatment resulted in decreased cell viability, accompanied by upregulation of ferroptosis markers SLC7A11 and GPX4, and elevated levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and total iron in a dose-dependent manner. NMN effectively rescued LPS-induced ferroptosis and improved cell viability in microglia. Co-administration of NMN and ferrostatin-1 significantly reduced proinflammatory cytokine production in microglia following the introduction of LPS stimuli. Mechanistically, NMN facilitated glutathione (GSH) production, and promoted resistance to lipid peroxidation in a GPX4-dependent manner, repressing cytokine transcription and protecting cells from ferroptosis. RNA sequencing elucidated the underlying mechanism of NMN-associated microglia ferroptosis under LPS induction. Furthermore, simultaneous injection of NMN ameliorated LPS-induced ferroptosis and neuroinflammation in mouse brains. The data from the present study indicated that NMN enhances GPX4-mediated ferroptosis defense against LPS-induced ferroptosis in microglia by recruiting GSH, thereby inhibiting neuroinflammation. Therefore, therapeutic approaches targeting ferroptosis in diseases using NMN should consider both its anti-ferroptosis and anti-inflammatory effects to achieve optimal outcomes, presenting promising strategies for treating neuroinflammation-related diseases or disorders.
2025-03-01 | GSE262303 | GEO
Project description:Inhibiting ferroptosis represents a promising strategy to combat ferroptosis-related diseases. Here we show that 428, a selenide-containing noscapine derivative, effectively inhibits ferroptosis in various cell lines by enhancing the stability and activity of GPX4. TRIM41 was identified as a novel E3 ubiquitin ligase of GPX4 and 428 was demonstrated to bind to the selenocysteine residue Sec46 of GPX4 via the formation of a transient and reversible Se-Se bond, thereby blocking the interaction between GPX4 and TRIM41, stabilizing GPX4 and enhancing its activity. This unique dynamic covalent binding mode was preliminarily validated by structure-activity relationship analysis and molecular docking studies. Importantly, we demonstrated that 428 treatment alleviates bleomycin-induced pulmonary fibrosis in vivo by inhibiting ferroptosis. Overall, our studies identified a novel stabilizer and activator of GPX4, offering a potential therapeutic approach for the treatment of ferroptosis-related diseases and uncovering a new mechanism for regulating GPX4 degradation.
2025-04-08 | PXD062710 |
Project description:Metastatic BRAFV600E colorectal cancer (CRC) confers poor prognosis and represents a therapeutic bottleneck. To identify resistance mechanisms of the mitogen-activated protein kinase (MAPK) pathway in BRAFV600E CRC, we perform genome-wide CRISPR-Cas9 screening and discover that targeting glutathione peroxidase 4 (GPX4) overcomes resistance to BRAF inhibitor (BRAFi) combined with or without epidermal growth factor receptor inhibitor (EGFRi) in BRAFV600E CRC. Specifically, BRAFi ± EGFRi upregulates GPX4 expression, which antagonizes therapy-induced ferroptosis. Moreover, polo-like kinase 1 (PLK1) substrate activation promotes PLK1 translocation to the nucleus, activating chromobox protein homolog 8 (CBX8) phosphorylation at Ser265 to drives GPX4 expression. Targeting PLK1 enhances BRAFi ± EGFRi inhibition and triggers ferroptosis in vitro, vivo, organoid, and patient-derived xenograft model. Collectively, we demonstrate a PLK1–CBX8–GPX4 signaling axis that relays the ferroptosis mechanism of therapeutic resistance and propose a clinically actionable strategy to overcome BRAFi ± EGFRi resistance in BRAFV600E CRC.
2025-02-28 | GSE283185 | GEO
Project description:Glutathione peroxidase 4 (GPX4) utilizes glutathione (GSH) to detoxify lipid peroxidation and
plays an essential role in inhibiting ferroptosis. As a selenoprotein, GPX4 protein synthesis is
highly inefficient and energetically costly. How cells coordinate GPX4 synthesis with nutrient
availability remains unclear. In this study, integrated proteomic and functional analyses reveal
that SLC7A11-mediated cystine uptake promotes not only GSH synthesis but also GPX4 protein synthesis. Mechanistically, cyst(e)ine activates mechanistic/mammalian target of rapamycin complex 1 (mTORC1) and promotes GPX4 protein synthesis at least partly through the mTORC1-4E-BP signaling axis. Pharmacologic inhibition of mTORC1 decreases GPX4 protein levels, sensitizes cancer cells to ferroptosis, and synergizes with ferroptosis inducers (FINs) to suppress patient-derived xenograft tumor growth in vivo. Together, our results reveal a hitherto unrecognized regulatory mechanism to coordinate GPX4 protein synthesis with cyst(e)ine availability and suggest to use the combination of mTORC1 inhibitors and FINs in cancer treatment.
2020-08-25 | MSV000086009 | MassIVE
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:Cadmium (Cd) is a toxic heavy metal that has a significant impact on the liver and kidneys, rendering them highly susceptible to its toxic effects. However, the precise mechanism remains uncertain. Mice were exposed to Cd resulting severe ferroptosis and liver tissue damage via regulating hepatic GPX4 levels. It is noteworthy that despite the considerably lower concentration of Cd in the kidney compared to the liver, the oxidative damage observed in the exposed mice was significantly more severe in the kidney. It was therefore postulated that hepatic disorders may engage in such hepatorenal communication, thereby leading to the pathological phenotypes of distant organs under conditions of Cd exposure. The results of the mechanistic studies indicated that Cd-induced hepatocyte exosomes, which contain a variety of miRNAs produced by hepatocytes, such as miR-2137, etc., are capable of targeting renal GPX4 and reducing the level of GPX4 in renal cells. This resulted in the occurrence of ferroptosis in the kidneys. Injection of the appropriate dosage of Cd-induced exosomes, derived from hepatocytes, is sufficient to induce kidney damage in vivo. Our data support the hypothesis that treatment with an antagomir targeting miR-2137 is capable of inhibiting this process. Moreover, our findings revealed that selenium (Se) supplementation was sufficient to protect against Cd-induced hepatic and renal toxicity by elevating the expression level of selenoprotein GPX4 in vivo. In conclusion, we have identified liver-derived exosomes and their implications for hepatorenal communication under Cd exposure. This provides a new target for understanding the mechanism of Cd-induced hepatorenal communication. Our findings indicate that exosomes may serve as biomarkers and potential therapeutic agents for the exposure of Cd toxicity.
2025-07-17 | GSE302882 | GEO