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Btg2 Inhibits the UFMylation of Fmo1 thus Restricting Taurine Synthesis and Exacerbating Ferroptosis in Hepatic Ischemia Reperfusion Injury in Mice

ABSTRACT: Hepatic ischemia‒reperfusion (I/R) injury (HIRI) represents a frequently occurring pathological condition during liver surgery, yet the mechanisms governing HIRI remain inadequately comprehended. This study intends to explore the role of B-cell translocation gene 2 (Btg2) in HIRI. We find that Btg2 expression is up-regulated following HIRI. We subsequently develop HIRl model utilizing hepatocyte-specific Btg2 transgenic over-expression and systemic Btg2 knockout male mice, discovering that Btg2 deletion mitigates hepatic inflammation and apoptosis. Furthermore, cellular experiments confirm that Btg2 knockdown alleviates inflammation and mitochondrial stress generated by hypoxia/reoxygenation (H/R) in primary hepatocytes. Metabolomics reveals that taurine metabolism is significantly impacted in the livers of Btg2-/- mice. Mechanistically, we demonstrate that Btg2 restricts the UFMylation of flavin-containing monooxygenase 1 (Fmo1), the essential enzyme for taurine synthesis, by the E3 ligase UFM1-specific ligase 1 (Ufl1), consequently facilitating the K48 ubiquitination-mediated degradation of Fmo1. Adeno-associated virus-mediated Fmo1 over-expression inhibits ferroptosis and HIRI significantly in vivo, while adenovirus-mediated Fmo1 over-expression mitigates ferroptosis and hypoxia/reoxygenation damage in vitro. Moreover, virtual screening of natural compounds reveals that Daturataturin A (DTA) inhibits Btg2 thus attenuating ferroptosis and HIRI sufficiently. These results propose that Btg2 may constitute a promising therapeutics target for HIRI.

ORGANISM(S): Mus Musculus

SUBMITTER: Zhongjun Wu

PROVIDER: PXD072917 | iProX | Sat Jan 10 00:00:00 GMT 2026

REPOSITORIES: iProX

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Btg2 Inhibits the UFMylation of Fmo1 thus Restricting Taurine Synthesis and Exacerbating Ferroptosis in Hepatic Ischemia-Reperfusion Injury in Mice

Project description:Hepatic ischemia‒reperfusion (I/R) injury (HIRI) represents a frequently occurring pathological phenomenon during liver surgery, yet the mechanisms governing HIRI remain inadequately comprehended. This study intends to explore the role of B-cell translocation gene 2 (Btg2) in HIRI. We find that Btg2 expression is up-regulated following HIRI. We subsequently develop an HIRl model utilizing hepatocyte-specific Btg2 transgenic over-expression and systemic Btg2 knockout male mice, discovering that Btg2 deletion mitigates inflammation and apoptosis. Furthermore, cellular experiments confirm that Btg2 knockdown alleviates inflammation and mitochondrial stress generated by hypoxia/reoxygenation (H/R). Metabolomics reveals enrichment of taurine metabolism pathway in the Btg2-/- mice. Mechanistically, we demonstrate that Btg2 restricts the UFMylation of flavin-containing monooxygenase 1 (Fmo1), the essential enzyme for taurine synthesis, by the E3 ligase UFM1-specific ligase 1 (Ufl1), consequently facilitating the K48 ubiquitination-mediated degradation of Fmo1. Adeno-associated virus-mediated Fmo1 over-expression inhibits ferroptosis and HIRI significantly in vivo, while adenovirus-mediated Btg2 over-expression mitigates ferroptosis and hypoxia/reoxygenation damage in vitro. Moreover, virtual screening of natural compounds reveals that Daturataturin A inhibits Btg2 and attenuates ferroptosis and HIRI sufficiently. These results propose that Btg2 may constitute a promising therapeutics target for HIRI.

2025-07-25 | PXD066631 |

Autophagy of OTUD5 Destabilizes GPX4 to Confer Ferroptosis-Dependent Kidney Injury

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

Acute Kidney Injury Following Fatty Liver Ischemia-Reperfusion Injury

Project description:To understand the roles of ferroptosis in subsequent acute kidney injury (AKI) following hepatic ischemia-reperfusion injury (hIRI) in steatosis livers. The hIRI was induced in mice fed either a high-fat, high-sucrose diet (HFD) or a normal diet (ND) to mimic the AKI commonly observed clinically after fatty liver transplantation. RNA sequencing was conducted to investigate the underlying mechanisms. We found that apoptosis and inflammation are the prominent kidney injury mechanisms following fatty liver IRI. Although ferroptosis may not be directly involved in the renal injury, anti-ferroptosis intervention mitigates AKI, supporting the concept that ferroptosis-mediated liver injury may serve as the primary upstream trigger in this context.

2025-11-21 | GSE309904 | GEO

High-throughput sequencing to investigate the expression and potential role of differentially expressed microRNAs in ischemia–reperfusion myocardial cells

Project description:MicroRNAs are closely associated with the pathogenesis of various diseases, but the relationship between miRNAs and myocardial ischemia–reperfusion (I/R) injury remains unclear. Therefore, we aimed to explore the role and function of miRNAs in I/R. We established hypoxia/reoxygenation (H/R) model to detect differentially expressed miRNAs using high-throughput sequencing in rat myocardial cell. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment were used to analyse the potential functions and signaling pathways of target genes. We further assessed the expression of miRNA, iron ions, reactive oxygen species, and ferroptosis markers. In the study, 113 differentially expressed miRNAs, comprising 76 and 37 up-regulated and down-regulated genes, respectively, were identified. These findings offer a novel perspective on I/R regulation, down-regulation of miRNA expression inhibits ferroptosis and alleviates myocardial damage.The specific mechanisms underlying the actions of it require further study.

2023-09-15 | GSE242888 | GEO

Sub-lethal stimulation of ferroptosis leads to trophoblast dysfunction

Project description:Ferroptosis is a recently identified program of regulated cell death, defined by excessive accumulation of hydroperoxy-arachidonoyl (C20:4)- or adrenoyl (C22:4)- phosphatidyl-ethanolamine (OOH-PE). The selenium-dependent glutathione peroxidase 4 (GPX4) inhibits ferroptosis, converting unstable ferroptotic lipid hydroperoxides to non-toxic lipid alcohols. The effect of GPX4 ablation is divergent among cells and tissues, suggesting that additional regulators may guard trophoblasts against ferroptosis. While placental oxidative stress and lipotoxicity are hallmarks of placental dysfunction, the possible role of ferroptosis in placental function has not been hitherto investigated. Here we found that placental dysfunction is associated with ferroptosis, and that inhibition of GPX4 causes trophoblast injury and ferroptosis in vitro and in vivo during mouse pregnancy. Importantly, we uncover a role for the phospholipase PLA2G6 (PNPLA9, iPLA2beta), known to metabolizes OOH-PE to lyso-PE and oxidized fatty acid, in mitigating ferroptosis induced by GPX4 inhibition in vitro or by hypoxia-reoxygenation injury in vivo. Together, we identified ferroptosis in the human and mouse placenta, and established a novel role for PLA2G6 in attenuating trophoblastic ferroptosis. Our data provide mechanistic insights to the ill-defined entity of placental lipotoxicity, and may inspire new therapeutic strategies that target PLA2G6 as a means to modulate ferroptosis in placental and non-placental tissue.

2020-09-27 | GSE147625 | GEO

Metabolite-protein covariation architecture identifies a cysteine shunt regulating liver cholesterol

Project description:Protein regulation of metabolic processes is foundational to biology. Here we develop a mass spectrometry-based approach that leverages genetic diversity to nominate functional relationships between 285 metabolites and 11,868 proteins in living tissues. This Metabolite Protein Covariation Architecture (MPCA) recapitulates protein-metabolite functional relationships mediated by direct physical interactions and local metabolic pathway regulation, while nominating 3,542 relationships not previously described. Using MPCA, we discover a mechanism of regulation over liver cysteine utilization and cholesterol handling, regulated by the poorly characterized protein leucine rich repeats-containing protein 58 (LRRC58). We show that LRRC58 is the substrate adaptor of an E3 ubiquitin ligase that mediates proteasomal degradation of CDO1, the rate-limiting enzyme of the hypotaurine-taurine pathway1. Cysteine abundance regulates LRRC58-mediated CDO1 degradation, and depletion of LRRC58 is sufficient to stabilize CDO1 to drive consumption of cysteine to produce taurine. Taurine is central to cholesterol handling by promoting its excretion from the liver2, and we show that depletion of LRRC58 in hepatocytes elevates cysteine flux to taurine, and is sufficient to lower hepatic cholesterol in mice. Uncovering a mechanism of LRRC58 regulation over the cysteine shunt to taurine exemplifies the utility of MPCA as a platform to identify modes of protein regulation of metabolic processes.

2025-07-28 | PXD065355 | Pride

Hypoxia-driven alterations in the B16 melanoma cell transcriptome account for a higher metastatic potential

Project description:Hypoxia-driven alterations in the B16 melanoma cell transcriptome account for a higher metastatic potential: evidence for a role of Ero1L We analyzed transcriptomic adaptations to hypoxia/reoxygenation in B16 melanoma cells. By Ero1L over- and down-expression in vivo, we identified this ER oxidase as an actor of tumor growth and metastasis take. In vitro culture of B16 submitted to hypoxia (oxygen rate less than 1%)

2013-08-01 | E-GEOD-14727 | biostudies-arrayexpress

Dynamics of mRNA abundance and translation in response to short and prolonged hypoxia and reoxygenation

Project description:Gene expression analysis of 7d-old Arabidopsis seedlings exposed to short term (2 h) hypoxia, long term (9 h) hypoxia, and 1 h reoxygenation after long term (9 h) hypoxia to evaluate the regulation of gene expression at the level of translation. Keywords: Time Course, hypoxia recovery, polysomal mRNA, IP RNA, polysomes, hypoxia stress, reoxygenation, translational control.

2008-07-22 | GSE9719 | GEO

Hypoxia-driven alterations in the B16 melanoma cell transcriptome account for a higher metastatic potential

2013-08-01 | GSE14727 | GEO

Gene expression profiling in MCF7 cell lines under hypoxia and reoxygenation

Project description:Purpose: Study hypoxia and reoxygenation induced changes in genome-wide gene expression Methods: Using the MCF7 breast epithelial adenocarcinoma cell line as a model, we studied epigenomic reprogramming as a function of fluctuating oxygen tension. To this end, we performed a transcriptomics analysis in MCF7 cells subjected to changes in oxygenation (i.e. acute hypoxia, chronic hypoxia, reoxygenation). Results: Global downregulation upon hypoxia; partial restore on reoxygenation. Conclusions: Our data show that oxygen availability dynamically regulates gene transcription.

2016-11-01 | GSE70805 | GEO

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