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: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
Project description:Ferroptosis, an iron-dependent form of programmed cell death, arises from the accumulation of lipid peroxides at toxic levels. Sorafenib, a first-line treatment for advanced hepatocellular carcinoma (HCC), shows limited clinical efficacy due to drug resistance. However, the mechanisms underlying Sorafenib resistance, especially related to ferroptosis, remain poorly understood. In this study, we extend our previous research by identifying activating transcription factor 7-interacting protein (ATF7IP) as a key inhibitor of ferroptosis. ATF7IP depletion promotes Sorafenib-induced ferroptosis, resulting in decreased cell viability, reduced cellular glutathione level, increased lipid peroxidation, and altered mitochondrial crista structure. Notably, ATF7IP knockdown showed cooperative effects with Sorafenib in inhibiting HCC growth in mice. Mechanistically, ATF7IP interacts with SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) to epigenetically silence the transcription of cytochrome b5 reductase 2 (CYB5R2), thereby reducing cellular Fe2+ levels. Meanwhile, ATF7IP inhibits Sorafenib-induced ferroptosis also by stabilizing the antioxidant sensor Parkinsonism-associated deglycase (PARK7) protein which preserves the transsulfuration pathway to produce glutathione (GSH). In conclusion, our findings identify ATF7IP as a critical ferroptosis inhibitor and represent ATF7IP as a novel therapeutic target for Sorafenib-based combination therapies of HCC.
2025-04-14 | GSE294091 | GEO