Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Ferroptosis Induction by DGAT1 Inhibition Enhances Cancer Immunotherapy

ABSTRACT: Ferroptosis, a form of regulated cell death driven by lipid peroxidation, has emerged as a promising mechanism in cancer therapy. However, the lack of clinically viable ferroptosis inducers has precluded its therapeutic evaluation in patients. Here, we demonstrate that inhibition of diacylglycerol O-acyltransferase 1 (DGAT1) induces a ferroptosis-like phenotype in cancer cells and enhances the efficacy of immune checkpoint blockade (ICB) therapy. In human cancer cohorts, low DGAT1 expression correlated with improved prognosis and elevated ferroptosis-associated gene signatures. In murine models, both genetic knockout and pharmacological inhibition of DGAT1 enhanced ICB therapy efficacy by promoting increased infiltration of cytotoxic T lymphocytes (CTLs). Mechanistically, DGAT1 inhibition reduced lipid droplet (LD) accumulation, triggering elevated lipid peroxidation, mitochondrial dysfunction, and reactive oxygen species (ROS) production. These events culminated in glutathione peroxidase 4 (GPX4) depletion and ferroptosis. Given the availability of clinical-stage DGAT1 inhibitors, our findings provide a strong rationale for repurposing these agents as ferroptosis inducers to enhance cancer immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE292109 | GEO | 2026/02/25

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

DGAT1 phosphoproteome and long-term proteome

Project description:Enhanced fatty acid (FA) synthesis and uptake underpin the sustained membrane biogenesis and ATP production required for melanoma cell growth and division1-4. However, to thrive, melanoma cells must avoid a potential reduction in cell growth signalling, rampant reactive oxygen species (ROS) generation, and the build-up of toxic lipid species that can accompany excess free FA5. Here, we uncover and address the significance of frequent amplification and up-regulation of the Diacylglycerol O-acyltransferase 1 (DGAT1) gene in melanoma, whose encoded product catalyses the final step of Triacyglyceride (TAG) synthesis. Consistent with the classification of DGAT1 as an oncogene, we found that forced DGAT1 expression in p53 mutant zebrafish melanocytes was sufficient to induce melanoma, and accelerated melanoma progression initiated by co-expression of oncogenic BRAF or NRAS. Regarding DGAT1 function in human melanoma cells, its depletion, or alternatively pharmacological inhibition, suppressed mTOR-S6K signalling and increased levels of acyl carnitine species— FA derivatives that are the limiting substrate for FA oxidation (FAO). In turn, increased FAO induced mitochondrial malfunction, ROS generation, and lipid peroxidation. However, the resultant oxidative stress induced NRF2 and SESTRIN2 (SESN2) expression, which limited the extent of cell death. Conversely, DGAT1 over-expression enhanced mTOR-S6K signalling and cell growth, and protected against ROS, particularly in hypoxic conditions. Together, our data establish DGAT1 as a bona fide oncogene essential in melanoma cells for enabling FA accumulation.

2023-03-10 | PXD017487 | Pride

Ferroptosis Induction by DGAT1 Inhibition Enhances Cancer Immunotherapy

Project description:Ferroptosis Induction by DGAT1 Inhibition Enhances Cancer Immunotherapy

| PRJNA1237218 | ENA

Ferroptotic cell death triggered by conjugated linolenic acids is mediated by ACSL1

Project description:Ferroptosis is associated with lipid hydroperoxides generated by oxidation of polyunsaturated acyl chains. Lipid hydroperoxides are reduced by glutathione peroxidase 4 (GPX4) and GPX4 inhibitors induce ferroptosis. However, the therapeutic potential of triggering ferroptosis in cancer cells with polyunsaturated fatty acids is unknown. We identified conjugated linoleates including α-eleostearic acid (αESA) as novel ferroptosis inducers. αESA did not alter GPX4 activity but was incorporated into cellular lipids and promoted lipid peroxidation and cell death in diverse cancer cell types. αESA-triggered death was mediated by acyl-CoA synthetase long-chain isoform 1, which promoted αESA incorporation into neutral lipids including triacylglycerols. Interfering with triacylglycerol biosynthesis suppressed ferroptosis triggered by αESA but not by GPX4 inhibition. Orally administered tung oil, naturally rich in αESA, limited tumor growth and metastasis with transcriptional changes consistent with ferroptosis. Overall, these findings illuminate a novel approach to ferroptosis, complementary to GPX4 inhibition, with therapeutic potential.

2021-02-08 | GSE162069 | GEO

Dgat1 detoxifies androgen receptor signaling to promote antitumor CD8+ T cell responses

Project description:The role of fatty acid (FA) oxidation 31 in T cell responses has been extensively studied, but whether FA esterification to triacylglycerol (TAG) regulates T cell exhaustion is unknown. Dgat1 catalyzes the rate-limiting step in TAGsynthesis. Here,we showthat deficiency in Dgat1 improvedmitochondrial metabolic fitness and expanded the pool of progenitors of CD8+ exhausted T (Tex) cells to sustain antitumor responses in femalemice. Inmalemice, however, Dgat1 deficiency synergized with androgen receptor (AR) signaling to cause FA peroxidation, endoplasmic reticulum (ER) stress, and Tex cell death. Deletion of Ar, overexpression of glutathione peroxidase 4 (Gpx4), or inhibition of ER stress-induced cell death rescued Dgat1-deficient CD8+ T cell survival and promoted antitumor responses in male mice. This study suggests that Dgat1 detoxifies AR signaling to protect against ER stress-induced cell death and maintain T cell stemness in males, and highlights sex-specific metabolic adaptations in the tumormicroenvironment.

2025-12-16 | GSE307220 | GEO

Obesity facilitated colon cancer progression is mediated by increased diacylglycerol o-acyltransferases 1 and 2 (DGAT1/2) levels

Project description:Background & Aims: The obesity epidemic is associated with increased colon cancer progression. As lipid droplets (LDs) fuel tumor growth, we aim to determine the significance of diacyltransferases, DGAT1/2, responsible for LDs biogenesis, in obesity-mediated colonic tumorigenesis. Methods: Human colon cancer samples, colon cancer cells, colonospheres, and ApcMin/+ colon cancer mouse model on a high-fat diet were employed. For DGAT1/2 inhibition, enzymatic inhibitors and siRNA were used. Expression, pathways, cell cycle, and growth were assessed. Bioinformatic analysis of CUT&RUN and RNAseq data was performed. Results: DGAT1/2 levels in human colon cancer tissue are significantly elevated with disease severity and obesity (vs normal). Their levels are increased in human colon cancer cells (vs non-transformed) and further enhanced by fatty acids prevalent in obesity; augmented DGAT2 expression is MYC-dependent. Inhibition of DGAT1/2 improves FOXO3 activity by attenuating PI3K, resulting in reduced MYC-dependent DGAT2 expression and LDs accumulation, suggesting feedback. This inhibition attenuated growth in colon cancer cells and colonospheres via FOXO3/p27kip1 cell cycle arrest and reduced colonic tumors in ApcMin/+ mice on a high-fat diet. Transcriptomic analysis revealed that DGAT1/2 inhibition targeted metabolic and tumorigenic pathways in human colon cancer and colon cancer crypts, stratifying human colon cancer samples from normal. Further analysis revealed that this inhibition is predictive of advanced disease-free state and survival in colon cancer patients. Conclusion: This is a novel mechanism of DGAT1/2-dependent metabolic and tumorigenic remodeling in obesity-facilitated colon cancer, which provides a platform for the future development of effective treatments for colon cancer patients.

2024-10-14 | GSE278787 | GEO

Obesity facilitated colon cancer progression is mediated by increased diacylglycerol o-acyltransferases 1 and 2 (DGAT1/2) levels [RNA-seq]

2024-10-14 | GSE278785 | GEO

Proteomic and phosphoproteomic landscape underlying DGAT1 inhibitor-ameliorated lipotoxicity in Min6 cells

Project description:This dataset provides a comprehensive proteomic and phosphoproteomic resource investigating the protective effects of DGAT1 inhibitors against lipotoxicity in pancreatic beta cells. Min6 cells were treated with palmitic acid (PA) to induce lipotoxicity, with or without co-treatment with the DGAT1 inhibitors. The data includes global protein expression and phosphorylation site changes, enabling the exploration of molecular mechanisms underlying PA-induced cellular stress (e.g., ER stress, inflammation) and its reversal by DGAT1 inhibition. This resource is valuable for researchers studying beta cell lipotoxicity, diabetes, lipid metabolism, and the role of DGAT1 and post-translational modifications in cell survival and ferroptosis.

2025-11-18 | PXD070881 |

DGAT1 Inhibitor-Induced Gene Expression in Mouse Skin

Project description:Inhibition of Diacylglycerol O-acyltransferase 1 (DGAT1) has been a mechanism of interest for metabolic disorders. DGAT1 inhibition has been shown to be a key regulator in an array of metabolic pathways; however, based on the DGAT1 KO mouse phenotype the anticipation is that pharmacological inhibition of DGAT1 could potentially lead to skin related adverse effects. One of the aims in developing small molecule DGAT1 inhibitors that target key metabolic tissues is to avoid activity on skin-localized DGAT1 enzyme. In this report we describe a modeling-based approach to identify molecules with physical properties leading to differential exposure distribution. In addition, we demonstrate histological and RNA based biomarker approaches that can detect sebaceous gland atrophy pre-clinically that could be used as potential biomarkers in a clinical setting. Mice were treated with DGAT1 inhibitors for 14 days and dorsal skin biopsies (3-5 mm^2) were taken. RNA was profiled on custom Affymetrix microarrays. The primary goal was to identify robust and consistent biomarkers of DGAT1 inibition in skin.

2014-02-20 | E-GEOD-49375 | biostudies-arrayexpress

DGAT1 Inhibitor-Induced Gene Expression in Mouse Skin

2014-02-20 | GSE49375 | GEO

RNA-seq of human pancreatic cancer cell line PANC-1 treated with RSL-3, N6F11, Fin56 and Erastin against untreated controls

Project description:Ferroptotic cell death is dependent on unrestricted lipid peroxidation rather than activation of apoptotic effector caspases. A large number of ferroptosis activators have been reported recently. We used gene sequencing to analyze the effects of four ferroptosis activators (RSL3, N6F11, Fin56 and Erastin) on global gene expression in human PDAC1 cell line.

2023-10-18 | E-MTAB-12241 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data