Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1194375 | ENA |
REPOSITORIES: ENA
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Project description:Protein tyrosine phosphatase mitochondrial 1 (PTPMT1), is a member of the protein tyrosine phosphatase superfamily localized on the mitochondrial inner membrane, and regulates the biosynthesis of cardiolipin. Given the important position of PTPMT1 in mitochondrial function and metabolism, pharmacological targeting of PTPMT1 is considered a promising manner in disease treatments. In this study, we mainly investigated the role of PTPMT1 in hepatocellular carcinoma (HCC) ferroptosis, a new type of cell death accompanied by significant iron accumulation and lipid peroxidation. Herein, the pharmacological inhibition of PTPMT1 was induced by alexidine dihydrochloride (AD, a dibiguanide compound).
2025-05-07 | PXD058606 | Pride
Project description:Liver tumors undergo profound metabolic reprogramming to support survival, proliferation, and metastasis. Through a metabolic library screen combined with network-level integration of transcriptomic and metabolomic data, we identified a regulatory role of L-2-hydroxyglutarate dehydrogenase (L2HGDH) and its substrate, L-2-hydroxyglutarate (L2HG), on ferroptosis in hepatocellular carcinoma (HCC), which exhibits a metabolic environment prone to L2HG accumulation. Mechanistically, L2HG was found to promote chromatin accessibility at ferroptosis-related gene loci. Specifically, L2HG conferred protection against ferroptosis by enhancing cystine uptake via NRF2/SLC7A11 activation, while concurrently sensitizing cells to ferroptosis through glutathione degradation via ATF4/CHAC1 induction. The ferroptosis-protective effect of L2HG was dependent on NRF2, the ablation of which restored near-normal metabolic profiles in a spontaneous liver tumor mouse model. These findings suggest that the metabolically accumulated L2HG plays a dual role in modulating both ferroptosis resistance and sensitivity, thereby influencing liver tumorigenesis. Targeting these metabolic axes may provide novel strategies for ferroptosis-based antitumor therapies.
2025-07-26 | GSE302217 | GEO
Project description:Ferroptosis constitutes a promising therapeutic strategy against cancer by efficiently targeting the highly tumorigenic and treatment-resistant cancer stem cells (CSCs). We previously showed that the lysosomal iron-targeting drug Salinomycin (Sal) was able to eliminate CSCs by triggering ferroptosis. Here, in a well-established breast CSCs model (human mammary epithelial HMLER CD24low/CD44high), we identified that pharmacological inhibition of mechanistic target of rapamycin (mTOR), suppresses Sal-induced ferroptosis. Mechanistically, mTOR inhibition modulates iron cellular flux and prevents the iron and ROS bursts induced by Sal. Besides, integration of multi-omics data identified mitochondria as a key target of Sal action. We demonstrated that mTOR inhibition prevents Sal-induced mitochondrial functional and structural alteration, and that Sal-induced metabolic plasticity is mainly dependent on the mTOR pathway. Overall, our findings provide experimental evidences on the detailed mechanisms of mTOR as a crucial effector of Sal-induced ferroptosis, and gives proof-of-concept that careful evaluation of such combination therapy (here mTOR and ferroptosis co-targeting) is required for effective treatment.
2023-12-20 | PXD041545 | Pride
Project description:Targeting mitochondrial structure sensitizes AML to Venetoclax
| PRJNA516226 | ENA
Project description:Despite the remarkable success of programmed death 1/PD-L1 inhibition in tumor therapy, only a minority of patients benefits from it. Previous studies suggest the anti-PD-1 treatment failure may attribute to the intrinsic functions of PD-L1 in cancer cells. Here, we established a genome-wide CRISPR synthetic lethality screen to systematic explore the PD-L1 intrinsic function in head and neck squamous cell carcinoma (HNSCC) cells. Ferroptosis related genes were identified to be essential for PD-L1 deficient cell viability. Genetic and pharmacological induction of ferroptosis accelerated cell death in PD-L1 knockout cells. PD-L1 knockout cells were also highly susceptible to immunogenic ferroptosis in vitro and in vivo. Mechanistically, nuclear PD-L1 transcriptionally activated SOD2 expression to maintain redox homeostasis. Importantly, the lower ROS and ferroptosis were observed in HNSCC patients with the higher expression of PD-L1. In summary, our study illustrates that PD-L1 confers ferroptosis resistance by activating SOD2-meidated redox homeostasis in HNSCC cells, indicating an enhanced therapeutic effect can be achieved by targeting the intrinsic PD-L1 function during immunotherapy.
2024-07-08 | GSE268534 | GEO
Project description:To study the mitochondrial stress response HRI-eIF2a-ATF4 signaling pathway in mitochondrial cardiomyopathy , we generated Ptpmt1 cardiomyocytes-specific Knockout mcie, Eif2a mutant mcie, Gcn2 Knockout mcie, and Hri Knockout mcie
2022-04-21 | GSE201042 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE35402: miRNA expression profiling of hepatocellular carcinoma induced by AAV in vivo gene targeting at the Rian locus GSE35403: mRNA expression profiling of hepatocellular carcinoma induced by AAV in vivo gene targeting at the Rian locus Refer to individual Series
2012-07-02 | E-GEOD-35404 | biostudies-arrayexpress
Project description:Resistance to Bruton’s tyrosine kinase inhibitors (BTKi) remains a major therapeutic challenge in B-cell malignancies, limiting treatment durability. We demonstrate BRG1-mediated chromatin remodeling as a major driver of BTKi resistance. We show that cancer-associated BRG1 ATPase domain mutations protect cells from BTKi-induced ferroptosis by limiting reactive oxygen species (ROS) production and labile iron. Mechanistically, the BRG1T910M mutation activates the unfolded protein response (UPR) via ATF4, leading to upregulation of MEF2B, a key suppressor of ferroptosis. MEF2B further inhibits mitochondrial respiration and thus prevent BTKi-induced mitophagy and ferroptosis. Pharmacological inhibition of BRG1 promotes ferroptosis by suppressing pro-survival B cell receptor (BCR) signaling and the ATF4-MEF2B axis. We show that a clinical stage BRG1 inhibitor restores ferroptosis in BTKi-resistant cells and synergizes with BTKi across various MCL models. Together we propose for co-targeting BRG1 and BTK in treatment of B-cell malignancies.
2025-09-01 | GSE305144 | GEO
Project description:Therapeutic resistance represents a bottleneck to treatment in advanced gastric cancer (GC). Ferroptosis is an iron-dependent form of non-apoptotic cell death and is associated with anti-cancer therapeutic efficacy. Further investigations are required to clarify the underlying mechanisms. Ferroptosis-resistant GC cell lines were constructed. Dysregulated mRNAs between ferroptosis-resistant and parental cell lines were identified. The expression of SOX13/SCAF1 was manipulated in GC cell lines where relevant biological and molecular analyses were performed. Molecular docking and computational screening were performed to screen potential inhibitors of SOX13. We showed that SOX13 boosts protein remodeling of electron transport chain (ETC) complexes by directly transactivating SCAF1. This leads to increased supercomplexes (SCs) assembly, mitochondrial respiration, mitochondrial energetics, NADPH production and chemo- and immune-resistance. Zanamivir, reverted the ferroptosis-resistant phenotype via directly targeting SOX13 and promoting TRIM25-mediated ubiquitination and degradation of SOX13. Overall, SOX13/SCAF1 are important in ferroptosis-resistance, and targeting SOX13 with zanamivir has therapeutic potential.
2023-11-17 | GSE247870 | GEO