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Project description:Effects of ferroptosis inhibition on lung transcriptomics in monocrotaline rats
| PRJNA1160920 | ENA
Project description:To seek ferroptosis related genes in liver cancer cells, we treated HepG2 cells using ferroptosis inducer Erastin and inhibitor Ferrostatin, respectively. We found that a subset of genes were up-regulated in Erastin treatment groups and down-regulated in Ferrostatin treatment groups, suggesting that these genes might be correlated with ferroptosis.
2019-06-10 | GSE104462 | 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:Anorectal malformation (ARM), a common congenital anomaly of the digestive tract, is a result of insufficient elongation of the urorectal septum. The cytoplasmic protein Receptor of Activated C-Kinase 1 (Rack1) is involved in embryonic neural development; however, its role in embryonic digestive tract development and ARM formation is unexplored. Our study explored the hindgut development and cell death mechanisms in ARM-affected rats using spatial transcriptome analysis. We induced ARM in rats by administering ethylenethiourea via gavage on gestational day (GD) 10. On GDs 14-16, embryos from both normal and ARM groups underwent spatial transcriptome sequencing, which identified key genes and signalling pathways. Rack1 exhibited significant interactions among differentially expressed genes on GDs 15 and 16. Reduced Rack1 expression in the ARM-affected hindgut, verified by Rack1 silencing in intestinal epithelial cells, led to increased P38 phosphorylation and activation of the MAPK signalling pathway. The suppression of this pathway downregulated Nqo1 and Gpx4 expression, resulting in elevated intracellular levels of ferrous ions, reactive oxygen species (ROS) and lipid peroxides. Downregulation of Gpx4 expression in the ARM hindgut, coupled with Rack1 co-localisation and consistent mitochondrial morphology, indicated ferroptosis. In summary, Rack1, acting as a hub gene, modulates ferrous ions, lipid peroxides, and ROS via the P38-MAPK/Nqo1/Gpx4 axis. This modulation induces ferroptosis in intestinal epithelial cells, potentially influencing hindgut development during ARM onset.
2026-01-01 | E-MTAB-16069 | biostudies-arrayexpress
Project description:Comparing the effects of artesunate versus DMSO in three DLBCL cell lines, we found a decrease in cell viability to 80%-60%. Over increasing artesunate dosage,we found increasing ROS generation and lipid peroxidation. In combination with the Ferrostatin-1 rescue experiment, we conclude that cell death induced by artesunate is ferroptotic. We compared the transcriptome of the U2932 cell line with and without 100µm artesunate in triplicate. A ferroptosis gene signature is shown to be enriched among the upregulated genes of this comparison. GPX4 protein expression was shown to be downregulated after artesunate in U2932 cells, but not in the rescue experiment with Ferrostatin-1. MT1G gene expression was identified as required for artesunate-mediated ferroptosis via targeted suppression by shRNAs. We present significantly decreased cell viability when combining artesunate with doxorubicin, suggesting a potential translation into clinic for treatment of ABC and GCB DLBCL.
2024-03-06 | GSE260741 | GEO
Project description:Purpose: 5-FU resistance is considered to be a possible reason for the failure of conventional drug treatment of colorectal cancer (CRC). Recently, salinomycin (SAL), as a selective inhibitor of cancer stem cells (CSCs), has been used to sensitize and attenuate a variety of solid tumor chemotherapy drugs. In our study, our goal was to combine SAL with 5-FU to explore whether increase the sensitivity of CRC to 5-FU and the molecular mechanism that involved in enhancing 5-FU sensitivity and promoting tumor cell chemotherapeutic death. Methods: ComboSyn software was used to study whether dual drug combinations synergistically promote each other and their dosage. CCK8, EdU and Annexin V/PI assays were used to study the cell proliferation and apoptosis of SW480 and HCT116 cells in response to SAL single-drug and dual-drug co-treatment. Cell cycle staining was used to assess cycle arrest. Wound healing and migration and invasion experiments were used to identify changes in migration and invasion capabilities under the influence of different drugs. Transcriptome sequencing is used to explore the molecular mechanisms of drugs. ROS fluorescence staining and MDA level measurement were used to confirm the changes in ferroptosis levels of SW480 and HCT116 cells after drug treatment. Nude xenograft mice were used to detect antitumor in vivo. Changes in the protein level expression of ferroptosis GPX4 and SLC7A11 were also determined in the treated cells.Results: SAL alone and combination of 5-FU were found to significantly increase cell mortality and apoptosis. At the same time, our results show that the blending of SAL and 5-FU not only inhibits the proliferation, migration, and invasion of CRC colorectal cancer cell lines in vivo and in vitro, but also promotes ferroptosis of CRC cell lines by downregulating the expression of GPX4 and SLC7A11. It may provide more and novel solutions and treatment perspectives for 5-FU or other drug-resistant chemotherapy strategies for CRC patients.Conclusions: SAL inhibiting colorectal cancer whose effect is achieved by reducing GPX4 and SLC7A11 protein levels to mediate ferroptosis activation in collaboration with 5-fluorouracil.
2025-06-21 | E-MTAB-15206 | biostudies-arrayexpress
Project description:Smooth muscle cell (SMC) loss is the characteristic feature in the pathogenesis of aortic dissection (AD), and ferroptosis is a novel iron-dependent regulated cell death driven by the excessive lipid peroxidation accumula_x0002_tion. However, whether targeting ferroptosis is an effective approach for SMC loss and AD treatment remains unclear. Here, we found that the iron level, ferroptosis-related molecules TFR, HOMX1, ferritin and the lipid peroxidation product 4-hydroxynonenal were increased in the aorta of AD. Then, we screened several inhibitors of histone methyltransferases and found that BRD4770 had a protective effect on cystine deprivation-, imidazole ketone erastin- or RSL3-induced ferroptosis of SMCs. The classic ferroptosis pathways, System Xc--GPX4, FSP1- CoQ10 and GCH1-BH4 pathways which were inhibited by ferroptosis inducers, were re-activated by BRD4770 via inhibiting mono-, di- and tri- methylated histone H3 at lysine 9 (H3K9me1/2/3). RNA-sequencing analysis revealed that there was a positive feedback regulation between ferroptosis and inflammatory response, and BRD4770 can reverse the effects of inflammation activation on ferroptosis. More importantly, treatment with BRD4770 attenuated aortic dilation and decreased morbidity and mortality in a β-Aminopropionitrile monofumarate-induced mouse AD model via inhibiting the inflammatory response, lipid peroxidation and fer_x0002_roptosis. Taken together, our findings demonstrate that ferroptosis is a novel and critical pathological mechanism that is involved in SMC loss and AD development. BRD4770 is a novel ferroptosis inhibitor and has equivalent protective effect to Ferrostatin-1 at the optimal concentration. Translating insights into the anti-ferroptosis ef_x0002_fects of BRD4770 may reveal a potential therapeutic approach for targeting SMC ferroptosis in AD.
2024-07-16 | GSE272018 | GEO
Project description:Liver cancer is one of the most lethal malignancies with an annual death of over 830,000 cases. Although targeted therapeutic drugs have achieved certain clinical efficacy, only sorafenib and lenvatinib are currently marketed as first-line targeted drugs to treat patients with advanced liver cancer. Therefore, developing more drugs are urgently needed. Ferroptosis is an iron-dependent programmed cell death (PCD) distinct from known PCDs including apoptosis, necrosis, and autophagy. Targeting ferroptosis is recognized as a promising potential therapeutic modality for liver cancer. Activating transcription factor 3 (ATF3) is an important ferroptosis inducer and targeting ATF3 offers a potential means to cancer therapy. In the present study, we reported for the first time a sophoridine derivative 6j with promising anti-liver cancer effects in vitro and in vivo. Compound 6j could induce liver cancer cells ferroptosis by promoting the accumulation of intracellular Fe2+, reactive oxygen species (ROS), and MDA. Inhibition of ferroptosis by ferrostatin-1 alleviated 6j induced accumulation of Fe2+, ROS, and MDA and restored cell viability. Further study revealed that compound 6j upregulated the expression of ATF3 via ER stress and knockdown of ATF3 by RNA interference attenuated 6j induced ferroptosis and cell proliferation inhibition. This study would provide new insights for the design of ferroptosis inducers and the development of anti-liver cancer drugs.
2023-08-23 | GSE237138 | GEO
Project description:Ferroptosis, a form of regulated cell death driven by lipid peroxidation, has emerged as a promising mechanism in cancer therapy. However, the lack of clinically viable ferroptosis inducers has precluded its therapeutic evaluation in patients. Here, we demonstrate that inhibition of diacylglycerol O-acyltransferase 1 (DGAT1) induces a ferroptosis-like phenotype in cancer cells and enhances the efficacy of immune checkpoint blockade (ICB) therapy. In human cancer cohorts, low DGAT1 expression correlated with improved prognosis and elevated ferroptosis-associated gene signatures. In murine models, both genetic knockout and pharmacological inhibition of DGAT1 enhanced ICB therapy efficacy by promoting increased infiltration of cytotoxic T lymphocytes (CTLs). Mechanistically, DGAT1 inhibition reduced lipid droplet (LD) accumulation, triggering elevated lipid peroxidation, mitochondrial dysfunction, and reactive oxygen species (ROS) production. These events culminated in glutathione peroxidase 4 (GPX4) depletion and ferroptosis. Given the availability of clinical-stage DGAT1 inhibitors, our findings provide a strong rationale for repurposing these agents as ferroptosis inducers to enhance cancer immunotherapy.
2026-02-25 | GSE292109 | GEO
Project description: Not available
| S-EPMC8866506 | biostudies-literature