Ontology highlight
ABSTRACT:
PROVIDER: PRJNA950129 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24010812_1.fastq.gz | Fastqsanger.gz | |||
| SRR24010812_2.fastq.gz | Fastqsanger.gz | |||
| SRR24010813_1.fastq.gz | Fastqsanger.gz | |||
| SRR24010813_2.fastq.gz | Fastqsanger.gz | |||
| SRR24010814_1.fastq.gz | Fastqsanger.gz |
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Project description:Ferroptosis is a specific type of lipid peroxide-mediated cell death which is crucial in tumor suppression. While the mitochondrial carrier homolog 2 (MTCH2) is implicated in lipid homeostasis and mitochondrial metabolism, its role in ferroptosis and colorectal cancer (CRC) remains uncharacterized. Here, we identified MTCH2 as a crucial regulator of ferroptosis in CRC progression. Clinically, high expression of MTCH2 in CRC tissues predicted poor prognosis. Functionally, loss of MTCH2 inhibited azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colorectal tumorigenesis in intestine-conditional Mtch2 knockout (Mtch2cKO) mice and led to accumulation of ferrous ion and enhanced ferroptosis of CRC in vitro and in vivo. Mechanistically, MTCH2 deficiency promoted the proteasome-dependent ubiquitination of E2F4 and attenuated transcriptional inhibition of transferrin receptor (TFRC) by E2F4, ultimately facilitating TFRC-mediated ferroptosis in CRC cells. Taken together, our study reveals the mechanism of MTCH2 deficiency induced ferroptosis to inhibit the progression of CRC, and supports a potential therapeutic strategy targeting the MTCH2/E2F4/TFRC signaling axis in CRC patients with liver metastasis.
2025-08-01 | GSE277185 | GEO
Project description:Loss of MTCH2 induces E2F4/TFRC-mediated ferroptosis in colorectal cancer
| PRJNA1161158 | ENA
Project description:Mitochondria play a critical role in initiating and amplifying ferroptosis. VDAC1 embedded in the mitochondrial outer membrane, exerts a crucial role in regulation of ferroptosis. However, the mechanisms of VDAC1 oligomerization in regulating ferroptosis are not well elucidated. Here, we identified that VSTM2L, a novel VDAC1 binding protein, is positively associated with prostate cancer (PCa) progression, and a key regulator of ferroptosis. Moreover, VSTM2L knockdown in PCa cells enhanced the sensibility of RSL3-induced ferroptosis. Mechanistically, VSTM2L forms complex with VDAC1 and HK2, enhancing their binding affinity and preventing VDAC1 oligomerization, thereby inhibiting ferroptosis and maintaining mitochondria homeostasis in vitro and in vivo. Collectively, our findings reveal a pivotal role for VSTM2L in driving ferroptosis resistance and highlight its potential as a ferroptosis-inducing therapeutic target for the treatment of PCa.
2025-05-07 | PXD052173 | Pride
Project description:Caseinolytic protease X (ClpX) is an unfoldase that forms the ClpXP complex with caseinolytic protease P (ClpP), playing a critical role in maintaining mitochondrial protein homeostasis. While targeting ClpP has emerged as a promising cancer intervention strategy, the biological function of ClpX in cancer remains largely unexplored. In this study, we identify elevated expression of CLPX in pancreatic ductal adenocarcinoma (PDAC), which correlates with poor patient prognosis. CLPX knockdown significantly inhibits cell proliferation and disrupts mitochondrial protein homeostasis in PDAC cells. This knockdown also induces mitochondrial oxidative stress, impairs oxidative phosphorylation, and activates the unfolded protein response. CLPX knockdown increases reactive oxygen species (ROS) levels, ferrous ion accumulation, lipid peroxidation, and elevates malonaldehyde content, thus promoting ferroptosis. Furthermore, screening of reported ATPase inhibitors reveals that MSC1094308 binds to ClpX, inhibiting ClpXP-mediated substrate degradation. MSC1094308 induces unfolded protein stress and ferroptosis in PDAC cells. Altogether, our findings suggest that ClpX inhibition represents a potent therapeutic strategy for combating PDAC.
2026-01-28 | GSE289242 | GEO
Project description:Knockout or inhibition of glutathione peroxidase 4 (GPX4) induces ferroptosis which has been proposed as a potential therapeutic strategy for cancer. Here we unexpectedly found that inducible knockout of GPX4 in tumor cells significantly promotes non-small cell lung cancer (NSCLC) progression in the autochthonous KrasLSL-G12D/+Lkb1fl/fl (KL) and KrasLSL-G12D/+Tp53fl/fl (KP) mouse models, whereas inducible overexpression of GPX4 in tumor cells had an opposite effect. Mechanistically, knockout of GPX4 in tumor cells results in the accumulation of triacylglycerol (TAG) that was stored in lipid droplets in tumor cells and the efflux of TAG that induces ferroptosis of macrophages in the tumor microenvironment (TME), thereby igniting an immunoinhibitory TME characterized by the dysfunction of anti-tumor T cells and the decrease of antigen-presenting macrophages. Consistently, treatment with liprostatin-1 or inducible overexpression of GPX4 in tumor cells significantly rescues the ferroptosis of macrophages and ignites the activation of T cells in the TME, thereby inhibiting NSCLC progression. These findings highlight a previously uncharacterized role of tumor cell-specific GPX4 in NSCLC progression by modulating TAG metabolism in the TME and provide potential therapeutic strategies for NSCLC.
2024-11-05 | GSE281159 | GEO
Project description:KRAS mutation activates multiple intracellular signalling pathways, leading to tumour development and progression. However, whether KRAS mutations are involved in regulating ferroptosis in cancer and the underlying mechanism remains unclear. Here, we constructed stable KRASWT and KRASG12D-mutant cell lines by transfecting wild-type (WT) or G12D plasmids into original KRAS WT cells and detected their cell viability under the treatment of ferroptosis inducer RSL3 or erastin. We found compared with WT cells, KRASG12D-mutated pancreatic and colorectal cancer cells presented greater viability and less cell death, along with lower levels of lipid peroxidation (LPO) and fewer damaged mitochondria, suggesting that the G12D mutation confers resistance to ferroptosis. Moreover, we found that KRASG12D mutated cancer cells demonstrated increased glycolysis and elevated lactate production, which was dependent on MEK-ERK-mediated L-lactate dehydrogenase A (LDHA) phosphorylation. Importantly, lactate supplementation in WT cells also resulted in ferroptosis resistance, indicating that G12D mutation-induced resistance to ferroptosis may be linked to lactate production. Mechanistically, G12D mutation-derived lactate accumulation induces Glutamate-cysteine ligase modifier (GCLM) lactylation, a process catalysed by Acetyl-CoA Acetyltransferase 2 (ACAT2). Inhibition of GCLM lactylation either through the mutation of the lactylation site or by knockdown of ACAT2 diminished the enzymatic activity of Glutamate-cysteine ligase (GCL) and suppressed Glutathione (GSH) synthesis. Ultimately, we found that ACAT2 knockdown can overcomes ferroptosis resistance in G12D-mutated cancer models in vivo. Thus, our study reveals a novel role for the G12D mutation in regulating GCLM lactylation and ferroptosis. Targeting GCLM lactylation may represent a promising strategy for overcoming ferroptosis resistance.
2025-05-07 | PXD062451 | Pride
Project description:Colorectal cancer (CRC) poses a severe global health threat with high incidence, mortality, and poor 5-year survival rates for advanced cases despite existing treatments. This study aims to explore the role of STRIP2 in CRC progression and its underlying mechanisms. Impact of STRIP2 on CRC in vitro was investigated via CRC cell proliferation, migration, invasion, and apoptosis. The in vivo impact was investigated via nude mice models. The role of STRIP2 in CRC was investigated via transcriptomic analysis, Western blot, Co-immunoprecipitation assays and ferroptosis validations. STRIP2 is overexpressed in CRC, driving malignant phenotypes in vitro and in vivo. Mechanically, STRIP2 stabilizes the IL17 downstream effector LCN2 by blocking its K48-linked ubiquitination and degradation, enhances anti-ferroptosis of CRC cells. Oe-STRIP2 suppresses ferroptosis, boosting proliferation and reducing oxidative stress; while si-STRIP2 induces the opposite effect. This study suggests STRIP2-mediated stabilization of LCN2 and enhances CRC cells ferroptosis resistance, thus promoting CRC cell survival and mediates malignant progression in CRC, which provides a novel link between STRIP2 and ferroptosis regulation in CRC.
2026-05-28 | GSE333323 | GEO
Project description:Hepatocellular carcinoma (HCC) remains one of the most lethal cancers, characterized by poor prognosis and low life expectancy. Unfortunately, there are very few molecular therapeutic options available for advanced HCC. Sorafenib is a current standard first-line treatment for advanced HCC, but drug resistance significantly limits its therapeutic efficacy. In this study, we identified ubiquitin-specific protease 22 (USP22) as the key regulator of HCC development and Sorafenib resistance. Analysis of TCGA databases revealed that USP22 is highly expressed in HCC tissues and is closely associated with poor patient prognosis. Our data further indicated that USP22 promotes the proliferation of HCC cells via deubiquitinating and stabilizing cyclin-dependent kinase 11B (CDK11B). Additionally, USP22 acts as a novel inducer of Sorafenib resistance and suppresses Sorafenib-triggered ferroptosis in HCC cells. It reduces the transcription of the transferrin receptor (TFRC) by decreasing H2BK120ub occupancy at TFRC transcription start site (TSS) downstream region, thereby inhibiting ferroptosis upon Sorafenib treatment. Finally, animal experiments confirmed the role of USP22 in promoting HCC cell growth and Sorafenib resistance in vivo. Taken together, our findings suggest that USP22 represents a promising prognostic biomarker and therapeutic target for HCC patients, particularly those with Sorafenib resistance.
2024-10-03 | GSE278685 | GEO
Project description:Hepatocellular carcinoma (HCC) remains one of the most lethal cancers, characterized by poor prognosis and low life expectancy. Unfortunately, there are very few molecular therapeutic options available for advanced HCC. Sorafenib is a current standard first-line treatment for advanced HCC, but drug resistance significantly limits its therapeutic efficacy. In this study, we identified ubiquitin-specific protease 22 (USP22) as the key regulator of HCC development and Sorafenib resistance. Analysis of TCGA databases revealed that USP22 is highly expressed in HCC tissues and is closely associated with poor patient prognosis. Our data further indicated that USP22 promotes the proliferation of HCC cells via deubiquitinating and stabilizing cyclin-dependent kinase 11B (CDK11B). Additionally, USP22 acts as a novel inducer of Sorafenib resistance and suppresses Sorafenib-triggered ferroptosis in HCC cells. It reduces the transcription of the transferrin receptor (TFRC) by decreasing H2BK120ub occupancy at TFRC transcription start site (TSS) downstream region, thereby inhibiting ferroptosis upon Sorafenib treatment. Finally, animal experiments confirmed the role of USP22 in promoting HCC cell growth and Sorafenib resistance in vivo. Taken together, our findings suggest that USP22 represents a promising prognostic biomarker and therapeutic target for HCC patients, particularly those with Sorafenib resistance.
2024-10-03 | GSE278684 | GEO
Project description:Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial distribution of renal GPX4-mediated ferroptosis and the molecular events causing GPX4 reduction during ischemia-reperfusion (I/R) remain largely unknown. Using spatial transcriptomics, we identify that GPX4 is situated at the interface of the inner cortex and outer medulla, a hyperactive ferroptosis site post-I/R injury. We show that OTU deubiquitinase 5 (OTUD5) is a GPX4-binding protein that confers ferroptosis resistance by stabilizing GPX4. During I/R, ferroptosis is induced by mTORC1-mediated autophagy, causing OTUD5 degradation and subsequent GPX4 decay. Functionally, OTUD5 deletion intensifies renal tubular cell ferroptosis and exacerbates acute kidney injury, while AAV-mediated OTUD5 delivery mitigates ferroptosis and promotes renal function recovery from I/R injury. In this work, our study highlights a new autophagy-dependent ferroptosis module: hypoxia/ischemia-induced OTUD5 autophagy triggers GPX4 degradation, offering a potential therapeutic avenue for I/R-related kidney diseases.
2023-11-29 | GSE244330 | GEO