Identification of lipid senolytics targeting senescent cells through ferroptosis induction
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PROVIDER: PRJNA1166889 | ENA |
REPOSITORIES: ENA
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Project description:Through phenotypic drug screening, we identified a novel class of lipid senolytics that selectively eliminated a broad range of senescent cells, reduced tissue senescence, and extended healthspan in mice. Extensive mechanistic studies reveal that these lipids induce ferroptotic cell death by exploiting the iron-rich and ROS-prone characteristics of senescent cells, offering a new therapeutic strategy to target senescence in aging and age-related diseases.
2024-10-07 | GSE278372 | GEO
Project description:Ferroptosis is an iron-dependent regulated cell death caused by the accumulation of lipid peroxidation for the uncontrolled metabolism. Serum, as the major medium for the cultured cells, resembles the contents of the extracellular fluid in vivo and provides biomolecules for cellular metabolism. The efficiency of ferroptosis induction is influenced by several factors including the extracellular environment. However, the effect of serum on ferroptosis remains largely unclear. We found that cells cultured in different serums have varying efficiencies in ferroptosis induction. By purifying and identifying active serum components, we discovered that serum protein apolipoprotein H (APOH) play essential role in inhibiting ferroptosis. Moreover, APOH activates the phosphoinositide 3-kinase (PI3K)/AKT-Sterol regulatory element-binding proteins (SREBPs) pathway. SREBPs upregulate the stearoyl-CoA desaturase (SCD) increasing cellular monounsaturated fatty acid-containing phospholipids (MUFA-PLs), leading to ferroptosis inhibition. Our findings indicate that APOH, as an extracellular protein, plays an important role in cellular lipid metabolism and inhibition of ferroptosis, thus may having therapeutic applications in cancer treatment and ferroptosis-related diseases.
2024-10-09 | GSE237178 | GEO
Project description:Ferroptosis is an iron-dependent form of cell death driven by biochemical and metabolic alterations resulting in oxidation within the lipid compartment. Calcium is a potent signaling molecule ascribed to diverse cellular processes including migration, neurotransmitter function, and cell death. Here we elucidate a crucial link between calcium homeostasis and ferroptotic cell death through the identification of the tetraspanin MS4A15. Ectopic MS4A15 expression specifically protects against ferroptosis by depleting endoplasmic reticulum stores. In an unexpected connection, prolonged calcium dysregulation stimulates fundamental remodeling to ferroptosis-resistant monounsaturated and plasmalogen lipid species. Application of this discovery revealed that augmenting luminal calcium sensitizes cancer cell lines previously refractory to ferroptosis. This finding provides a unique mechanistic basis for ferroptosis sensitivity and resolves a long-standing query into the role of calcium in oxidative cell death. Manipulating calcium homeostasis offers an unprecedented strategy for overcoming therapy resistance in cancer.
2021-10-09 | GSE160574 | GEO
Project description:The discovery of effective senolytics offers a promising approach for treating many age-related diseases. In this study, we employed a phenotypic drug discovery approach, combining drug screening and drug design, to identify and develop novel senolytic agents based on the flavonoid fisetin. We successfully developed two novel flavonoid analogs, SR29384 and SR31133, which demonstrated significantly enhanced senolytic activities compared to fisetin. These analogs showed broad-spectrum efficacy in eliminating various senescent cell types, reducing tissue senescence, extending healthspan in mice, and prolonging lifespan in Drosophila. Through RNA sequencing, machine learning, and computational screening, our mechanistic studies suggest that these novel flavonoid senolytics may target PARP1, BCL2L1, and CDK2 to induce senescent cell death.
2024-10-27 | GSE279349 | 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:Acquired and primary therapy resistance remain a major hurdle in clinical treatment of multiple myeloma (MM). Despite the availability of broad spectrum anti-cancer drugs, most MM patients eventually relapse and become refractory to current treatments. Therefore, we explored whether therapy-resistant MM cells are sensitive to ferroptosis induction, an iron-catalyzed mode of cell death associated with increased lipid peroxidation. In this study, we exposed glucocorticoid-resistant MM1R and glucocorticoid-sensitive MM1S cells to ferroptosis inducers RSL3 and evaluated their transcriptional changes via RNA sequencing. Compared to untreated controls, ferroptotic RSL3-treated cells displayed a significant upregulation of genes involved in inflammation, kinase signaling, cellular stress, and cell death pathways. Pre-treatment with ferroptosis inhibitor Fer-1 partly reverted these RSL3-induced transcriptional changes and revealed that especially genes involved in metal binding, nuclear receptor signaling, chromatin remodeling, and gene transcription regulation are pivotal for ferroptosis induction. Overall, these findings suggest that ferroptosis effectively targets MM1 cells and that RSL3-mediated ferroptosis triggers similar oxidative stress and cell death pathways in both MM1R and MM1S cells, irrespective of their glucocorticoid-sensitivity status.
2021-11-08 | GSE182638 | GEO
Project description:Senescence is a cellular state linked to aging and age-onset disease across many mammalian species. Acutely, senescent cells promote wound healing and prevent tumor formation; but they are also pro-inflammatory, thus chronically exacerbate tissue decline. While senescent cells are active targets for anti-aging therapy, why these cells form in vivo, how they affect tissue aging, and the impact of their elimination remain unclear. Here we identify naturally-occurring senescent glia in aged Drosophila brains and decipher their origin and influence. Using AP1 activity to screen for senescence, we determine that senescent glia can appear in response to neuronal mitochondrial dysfunction. In turn, senescent glia promote lipid accumulation in non-senescent glia; similar effects are seen in senescent human fibroblasts in culture. Targeting AP1 activity in senescent glia mitigates senescence biomarkers, extends fly life and health span, and prevents lipid accumulation. However, these benefits come at the cost of increased oxidative damage in the brain, and neuronal mitochondrial function remains poor. Altogether, our results map the trajectory of naturally-occurring senescent glia in vivo and indicate that these cells link key aging phenomena: mitochondrial dysfunction and lipid accumulation.
2024-05-24 | GSE263928 | GEO
Project description:Ferroptosis is an iron-dependent cell death mechanism characterized by an accumulation of toxic lipid peroxides and membrane rupture. The glutathione dependent enzyme, GPX4 (glutathione peroxidase 4), prevents ferroptosis by reducing these lipid peroxides into non-toxic lipid alcohols. Ferroptosis induction by GPX4 inhibition has emerged as a vulnerability of cancer cells, thus highlighting the need to identify ferroptosis regulators that may be exploited therapeutically. Through genome-wide screens and a series of genetic, genomic, and quantitative imaging approaches, we identify the SWI-SNF ATPases BRM and BRG1 as ferroptosis suppressors. Mechanistically, they directly bind to and catalytically increase chromatin accessibility at NRF2 target loci, thus boosting NRF2 transcriptional output. This primes cells to counter lipid peroxidation and confers resistance to GPX4 inhibition and ferroptosis. Importantly, we demonstrate that the BRM/BRG1-ferroptosis connection can be leveraged to enhance the paralog dependency of BRG1-mutant lung cancer cells on BRM, especially in lines that are less sensitive to BRM inhibition or degradation. Our data reveal ferroptosis induction as a potential avenue for broadening the efficacy of BRM degraders/inhibitors and define a specific genetic context for exploiting GPX4 dependency.
2024-09-22 | GSE266343 | GEO
Project description:Ferroptosis is an iron-dependent cell death mechanism characterized by an accumulation of toxic lipid peroxides and membrane rupture. The glutathione dependent enzyme, GPX4 (glutathione peroxidase 4), prevents ferroptosis by reducing these lipid peroxides into non-toxic lipid alcohols. Ferroptosis induction by GPX4 inhibition has emerged as a vulnerability of cancer cells, thus highlighting the need to identify ferroptosis regulators that may be exploited therapeutically. Through genome-wide screens and a series of genetic, genomic, and quantitative imaging approaches, we identify the SWI-SNF ATPases BRM and BRG1 as ferroptosis suppressors. Mechanistically, they directly bind to and catalytically increase chromatin accessibility at NRF2 target loci, thus boosting NRF2 transcriptional output. This primes cells to counter lipid peroxidation and confers resistance to GPX4 inhibition and ferroptosis. Importantly, we demonstrate that the BRM/BRG1-ferroptosis connection can be leveraged to enhance the paralog dependency of BRG1-mutant lung cancer cells on BRM, especially in lines that are less sensitive to BRM inhibition or degradation. Our data reveal ferroptosis induction as a potential avenue for broadening the efficacy of BRM degraders/inhibitors and define a specific genetic context for exploiting GPX4 dependency.
2024-07-01 | GSE245247 | GEO
Project description:Ferroptosis is an iron-dependent cell death mechanism characterized by an accumulation of toxic lipid peroxides and membrane rupture. The glutathione dependent enzyme, GPX4 (glutathione peroxidase 4), prevents ferroptosis by reducing these lipid peroxides into non-toxic lipid alcohols. Ferroptosis induction by GPX4 inhibition has emerged as a vulnerability of cancer cells, thus highlighting the need to identify ferroptosis regulators that may be exploited therapeutically. Through genome-wide screens and a series of genetic, genomic, and quantitative imaging approaches, we identify the SWI-SNF ATPases BRM and BRG1 as ferroptosis suppressors. Mechanistically, they directly bind to and catalytically increase chromatin accessibility at NRF2 target loci, thus boosting NRF2 transcriptional output. This primes cells to counter lipid peroxidation and confers resistance to GPX4 inhibition and ferroptosis. Importantly, we demonstrate that the BRM/BRG1-ferroptosis connection can be leveraged to enhance the paralog dependency of BRG1-mutant lung cancer cells on BRM, especially in lines that are less sensitive to BRM inhibition or degradation. Our data reveal ferroptosis induction as a potential avenue for broadening the efficacy of BRM degraders/inhibitors and define a specific genetic context for exploiting GPX4 dependency.
2024-07-01 | GSE245246 | GEO