Gpx4 prevents Treg-cell lipid peroxidation and ferroptosis in promoting immune homeostasis and tumor immune escape
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ABSTRACT:
PROVIDER: PRJNA672969 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR12926400_1.fastq.gz | Fastqsanger.gz | |||
| SRR12926400_2.fastq.gz | Fastqsanger.gz | |||
| SRR12926401_1.fastq.gz | Fastqsanger.gz | |||
| SRR12926401_2.fastq.gz | Fastqsanger.gz | |||
| SRR12926402_1.fastq.gz | Fastqsanger.gz |
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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: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:Gpx4 regulates iNKT cell homeostasis and function by preventing lipid peroxidation and ferroptosis
| PRJNA1126732 | ENA
Project description:Background: Small cell lung cancer (SCLC) is a high-grade and aggressive neuroendocrine carcinoma that remains incurable due to the emergence of drug resistance and frequent relapse. This study aimed to clarify the therapeutic potential and detailed mechanism of altretamine against SCLC.Methods: Altretamine-triggered cytotoxicity and lipid peroxidation were determined by EdU, FerroOrange probes, etc. GPX4 promoter methylation was evaluated by Methylation-specific PCR, chromatin immunoprecipitation, etc. Altretamine-induced GPX4 degradation was examined by bio-layer interferometry, immunoprecipitation, etc. Results: Altretamine mainly initiates ferroptosis in SCLC cells, accompanied by accumulation of intracellular ROS and lipid peroxidation. Mechanistically, altretamine facilitated the binding of DNMT3A to GPX4 promoter, leading to DNA methylation of GPX4 gene and subsequent transcriptional repression. Moreover, altretamine directly bound to GPX4 protein and accelerated the lysosomal degradation of GPX4 protein in a HSC70-dependent manner. Inhibition of DNA demethylation by inactivating Ten-eleven translocation (TET) proteins synergistically strengthened the anti-SCLC activity of altretamine.Conclusions: Our findings revealed the first time that altretamine induced ferroptotic cell death by promoting DNMT3A-mediated epigenetic silencing of GPX4 gene and HSC70-mediated lysosomal degradation of GPX4 protein in SCLC cells. Altretamine alone or in combination with TET inhibitors is a valuable and credible strategy for the clinical treatment of SCLC.
2026-09-23 | GSE325021 | GEO
Project description:Aims: Oligoasthenozoospermia (OAS) causes male infertility. However, the etiology and pathogenesis of OAS are unclear, and specific therapy is lacking. Ferroptosis contributes to the progress of various diseases; however, its role in OAS is unknown. This study aimed to explore the mechanism of OAS and to find effective treatments. Results: Human OAS sperm exhibits biochemical and morphological hallmarks of ferroptosis. Ferroptosis represents a crucial role in OAS induced by cyclophosphamide (CP) of mice in vivo, and inhibiting ferroptosis can effectively improve OAS. Further search for safe, stable and clinically applicable of natural compounds found Salidroside （Sal）improved the sperm quality of OAS by attenuates ferroptosis-mediated lipid peroxidation in germ cells by increasing the expression of GPX4, and thus ameliorates OAS in vivo. To further investigate at which stage of spermatogenesis Sal acts, the result revealed that Sal increases the expression of GPX4 starting from primary spermatocytes gradually by immunohistochemistry. In vitro, we verified the above results in vivo using a mouse spermatocytes cell line, GC-2 cells. Mechanistically, integrated RNA-Seq and bioinformatic analysis showed that Sal likely promotes GPX4 expression by inhibiting NF-κB Pathway, thereby inhibiting ferroptosis. Innovation: Our findings support the view that ferroptosis plays an important role in patients with OAS, and provide convincing evidence that Sal ameliorates OAS by inhibiting ferroptosis-mediated lipid peroxidation via NF-κB pathway suppression. Conclusions: Thus, ferroptosis plays an important role in OAS, and Sal could ameliorate OAS by attenuating ferroptosis-mediated lipid peroxidation via NF-κB pathway inhibition.
2024-12-01 | GSE249162 | 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:Background: Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation (LPO), represents a promising therapeutic strategy. Magnolia officinalis, a traditional herb for resolving dampness and phlegm, is known to modulate cellular metabolism. While magnolol (MAG), a bioactive neolignan from Magnolia officinalis, shows anti-TNBC activity, its role in inducing ferroptosis remains unexplored. Methods: Anti-TNBC effects of MAG were assessed in MDA-MB-231 and 4T1 cells via viability, apoptosis, and ferroptosis assays (intracellular Fe²⁺, LPO, GSH). Target identification employed network pharmacology, RNA-seq, surface plasmon resonance, and pull-down assays. Mechanisms were validated using siRNA/overexpression, Co-IP, and immunofluorescence. In vivo efficacy was evaluated in xenograft models. Results: MAG inhibited proliferation and induced apoptosis and ferroptosis in TNBC cells, evidenced by elevated Fe²⁺ and lipid peroxidation, depleted GSH, downregulated SLC7A11/GPX4, and mitochondrial shrinkage effects reversed by ferroptosis inhibitors. MAG directly bound and suppressed transcription factor ETS2. ETS2 knockdown sensitized cells to MAG-induced ferroptosis, while its overexpression restored SLC7A11/GPX4 expression and conferred resistance. Mechanistically, ETS2 transcriptionally regulated SLC7A11, and MAG enhanced ETS2-SLC7A11 protein interaction. In vivo, MAG significantly suppressed tumor growth with low toxicity and downregulated ETS2, SLC7A11, and GPX4. Conclusions: MAG induces ferroptosis in MDA-MB-231 cells, which may be mediated by targeting the ETS2/SLC7A11/GPX4 signaling axis, providing mechanistic insights into its anti-TNBC activity.
2026-07-27 | GSE341147 | GEO
Project description:ARID1A, a subunit of the SWI/SNF chromatin-remodeling complex, functions as a tumor suppressor in various cancer types. Owing to its high frequency of inactivating mutations, ARID1A has emerged as a promising target for the development of anticancer drugs. In this study, we report that ARID1A-deficient colorectal cancer (CRC) cells induce synthetic lethality when treated with inhibitors of c-MET receptor tyrosine kinase. c-MET specific inhibitor PHA-665752 as well as two other FDA-approved drugs, crizotinib and cabozantinib, selectively inhibited the growth of ARID1A-deficient CRC cells in vitro and in xenograft tumor models. Mechanistically, we identified triple genetic interactions between ARID1A, c-MET, and GPX4 in CRC cells, where GPX4, a key regulator of ferroptosis, is a common transcription target of ARID1A and c-MET signaling. ARID1A inactivation significantly downregulated both c-MET and GPX4 levels, and the c-MET inhibitor further diminished GPX4 levels in ARID1A-deficient CRC cells, leading to increased lipid peroxidation and glutathione depletion, ultimately inducing ferroptosis. This study reveals a novel synthetic lethal relationship between ARID1A and c-MET signaling in promoting ferroptosis and proposes c-MET inhibitors as a potential therapeutic strategy for ARID1A-deficient CRC.
2026-01-01 | GSE286216 | GEO
Project description:Context: Ginkgolic acid (GAC), one of the major active constituents of Ginkgo biloba L. (Ginkgoaceae) extract, has been reported as a potential anticancer drugs. Objective: To investigate the effect of GAC on the viability of Human hepatocellular carcinoma (HCC) cells and its underlying mechanisms. Materials and methods: Human HCC cell lines and an orthotopic HCC mouse model were employed. RNA sequencing, drug affinity responsive target stability (DARTS) with LC-MS/MS, protein–protein interaction analysis, molecular docking, and cellular thermal shift assay (CETSA) were used to identify and validate GAC targets. Ferroptosis was evaluated by BODIPY probes, Annexin-V/PI staining, Western blotting, malondialdehyde (MDA), GSH/GSSG assays, and transmission electron microscopy (TEM). Cell viability was assessed by CCK-8 and colony formation assays. HSPA8 knockdown, mutant, and KFERQ-reporter cells were generated to investigate the role of HSPA8 and chaperone-mediated autophagy (CMA). Results: GAC effectively inhibits the viability of HCC by triggering ferroptosis. HSPA8 was identified as the directly target of GAC. The binding of GAC with HSPA8 enhancing its interaction with glutathione peroxidase 4 (GPX4), which leads to the degradation of GPX4 via CMA. This process depleted glutathione (GSH) and caused lipid peroxidation, finally inducing ferroptosis in HCC cells. Furthermore, GAC suppressed tumor growth in an orthotopic HCC model, increased lipid peroxidation and GPX4 degradation in tumor tissues. Discussion and conclusions: Our results revealed a novel mechanism by which GAC induces ferroptosis in HCC cells through direct targeting HSPA8 and promoting CMA-dependent GPX4 degradation. These findings demonstrate the potential of GAC as therapeutic approaches for HCC.
2026-04-01 | GSE317008 | 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