Differential Contributions of Distinct Free Radical Peroxidation Mechanisms to the Induction of Ferroptosis
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ABSTRACT:
PROVIDER: PRJNA930406 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23303600_1.fastq.gz | Fastqsanger.gz | |||
| SRR23303600_2.fastq.gz | Fastqsanger.gz | |||
| SRR23303601_1.fastq.gz | Fastqsanger.gz | |||
| SRR23303601_2.fastq.gz | Fastqsanger.gz | |||
| SRR23303602_1.fastq.gz | Fastqsanger.gz |
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Project description:Ferroptosis is a form of regulated cell death driven by lipid peroxidation of polyunsaturated fatty acids (PUFAs). Endogenous PUFAs are nonconjugated PUFAs and their peroxidation proceeds via the hydrogen-atom transfer (HAT) mechanism. We previously reported that lipids with conjugated double bonds undergo lipid peroxidation mostly via a different mechanism, peroxyl radical addition (PRA), and were much more readily oxidizable than nonconjugated ones. In this study, we aim to elucidate the effects of various unsaturated lipids in sensitizing ferroptosis. We found that while some peroxidation-reactive lipids, such as 7-dehydrocholesterol, vitamins D3 and A, and coenzyme Q10, suppress ferroptosis, both nonconjugated and conjugated PUFAs enhanced cell death induced by RSL3, a ferroptosis inducer. Importantly, we showed that conjugated linolenic acid (CLA 18:3) could act as a ferroptosis inducer by itself and conjugated linoleic acid (CLA 18:2) was more potent in sensitizing cells to RSL3-induced cell death than any nonconjugated PUFAs. We next sought to elucidate the mechanism underlying the different ferroptosis-inducing potency of conjugated and nonconjugated PUFAs. Lipidomics revealed that conjugated and nonconjugated PUFAs are incorporated into distinct cellular lipid species. Furthermore, the different peroxidation mechanisms predict the formation of higher levels of reactive electrophilic aldehydes from conjugated PUFAs than nonconjugated PUFAs, which was confirmed by aldehyde-trapping and mass spectrometry. RNA sequencing revealed that protein processing in the endoplasmic reticulum and proteasome are among the most significantly upregulated pathways in cells treated with CLA 18:3, suggesting increased ER stress and activation of unfolded protein response. Significantly, using click chemistry, we observed increased protein adduction by oxidized lipids in cells treated with an alkynylated CLA 18:2 probe. These results suggest that protein damage by lipid electrophiles is a key step in ferroptosis.
2023-04-17 | GSE224249 | GEO
Project description:Ferroptosis is a form of regulated cell death driven
| S-EPMC10131203 | biostudies-literature
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: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:Purpose: Gastric cancer remains one of the deadliest neoplasms worldwide, with a high need for new therapeutic options. Efficacies of targeted therapies are often limited owing to the inter- and intratumoral heterogeneity of gastric cancer. Thus, drugs with broader mechanisms of action rather than relying on the inhibition of a single specific oncogene are needed. Preclinical studies have identified histone deacetylases (HDAC) and their respective isoforms as potential therapeutic targets in gastric cancer. However, clinical efficacies are moderate and the mechanism(s) of action of HDAC inhibitors (HDACi) are only partially understood. Methods: In a panel of gastric cancer cell lines with different molecular characteristics, tumor cell inhibitory effects of different HDACi were studied. Lipid peroxidation levels were measured using flow cytometry. Proteome analysis was performed for the in-depth characterization of molecular alterations upon HDAC inhibition. HDACi effects on important ferroptosis genes were validated on the mRNA (RT-qPCR) and protein level (Western Blot). Results: Upon HDACi treatment, lipid peroxidation levels were found increased in all tested cell lines. Class-I HDACi (VK1, entinostat) showed the same toxicity profile as the pan-HDACi vorinostat. Proteome analysis revealed significant and concordant alterations in the expression of proteins related to ferroptosis induction. Key enzymes like ACSL4, POR or SLC7A11 showed distinct alterations in their expression patterns, providing an explanation for the increased lipid peroxidation. Alterations of POR and SLC7A11 levels upon treatment were also confirmed in primary human gastric cancer tissue cultures as relevant ex vivo model. Conclusion: We identify the induction of ferroptosis as a new mechanism of action of class-I HDACi in gastric cancer. Notably, these findings were independent of the genetic background of the cell lines, thus introducing HDAC inhibition as a more general therapeutic principle besides other, less broadly usable targeted drugs.
2024-05-21 | PXD050328 | Pride
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:Ferroptosis is a form of regulated cell death characterized by oxidative injury-induced lipid peroxidation. However, the detailed protein post-translational modification regulatory mechanism of ferroptosis remains largely unknown. Here, we report that E1A binding protein P300 (EP300) acetyltransferase promotes ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cells via the acetylation of heat shock protein family A (Hsp70) member 5 (HSPA5, also known as GRP78 or BIP) on the site of K353. Acetylated HSPA5 loses its ability to inhibit lipid peroxidation and subsequent ferroptotic cell death. Genetic or pharmacological inhibition of EP300-mediated HSPA5 acetylation on K353 increases PDAC cell resistance to ferroptosis. Moreover, histone deacetylase 6 (HDAC6) limits HSPA5 acetylation and subsequent ferroptosis.
2023-10-24 | PXD039998 | Pride
Project description:Therapy resistance and metastasis, the most fatal steps in cancer, are often triggered by a (partial) activation of the epithelial-mesenchymal-transition (EMT)-program. A mesenchymal phenotype predisposes to ferroptosis, a cell death pathway exerted by an iron and oxygen-radical mediated peroxidation of phospholipids containing polyunsaturated fatty acids (PUFAs). We here describe that various forms of EMT-activation, including TGFB-stimulation, increase ferroptosis-susceptibility in cancer cells, which depends on the EMT-transcription factor Zeb1. Among other effects, we demonstrate that Zeb1 increases the ratio of phospholipids containing pro-ferroptotic PUFAs over cyto-protective monounsaturated fatty acids (MUFAs) and modulates the expression of underlying crucial lipogenic enzymes (and ACSL4). Pharmacological inhibition of selected lipogenic enzymes (SCD and FADS2) allows the manipulation of ferroptosis-sensitivity in a Zeb1-dependent manner. Our data are of potential translational relevance and suggest a combination of ferroptosis-activators and SCD-inhibitors for the treatment of aggressive cancers expressing Zeb1, which might also be a useful predictive marker for such a combination therapy
2024-07-05 | GSE264671 | GEO
Project description:Ferroptosis is a unique iron-dependent form of non-apoptotic cell death characterized by devastating lipid peroxidation. Whilst growing evidence suggests that ferroptosis is a type of autophagy-dependent cell death, the underlying molecular mechanisms regulating ferroptosis are largely unknown. In this study, through an unbiased RNA-sequencing screening, we demonstrate the activation of a multi-faceted tumor-suppressor protein Par-4/PAWR during ferroptosis. Functional studies reveal that genetic depletion of Par-4 effectively blocks ferroptosis, whereas Par-4 overexpression sensitizes cells to undergo ferroptosis. More importantly, we have determined that Par-4-triggered ferroptosis is mechanistically driven by the autophagic machinery. Upregulation of Par-4 promotes activation of ferritinophagy (autophagic degradation of ferritin) via the nuclear receptor co-activator 4 (NCOA4), resulting in excessive release of free labile iron and, hence, enhanced lipid peroxidation and ferroptosis. Inhibition of Par-4 dramatically suppresses the NCOA4-mediated ferritinophagy signaling axis. Our results also establish that Par-4 activation positively correlates with reactive oxygen species (ROS) production, which is critical for ferritinophagy-mediated ferroptosis. Furthermore, Par-4 knockdown effectively blocked ferroptosis-mediated tumor suppression in the mouse xenograft models. Collectively, these findings reveal that Par-4 has a crucial role in ferroptosis, which could be further exploited for cancer therapy.
2024-05-24 | GSE267823 | GEO
Project description:Gpx4 regulates iNKT cell homeostasis and function by preventing lipid peroxidation and ferroptosis
| PRJNA1126732 | ENA