Lactate dehydrogenase B noncanonically promotes ferroptosis defense in KRAS-driven lung cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE224098 | GEO | 2024/12/04
REPOSITORIES: GEO
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Project description:Lactate dehydrogenase B noncanonically promotes ferroptosis defense in KRAS-driven lung cancer
| PRJNA929898 | ENA
Project description:Reactive oxygen species (ROS) play a crucial role in lipid peroxidation and the initiation of ferroptosis, significantly affecting chemotherapeutic drug resistance. However, the mechanisms by which ROS function and are sensed remain poorly understood. In this study, we identified O-GlcNAc transferase (OGT), a key enzyme in protein O-GlcNAcylation, as a sensor for ROS induced by ferroptosis. The ROS-induced oxidation of OGT at C845 in its catalytic domain activates the enzyme. Once activated, OGT O-GlcNAcylates FOXK2, enhancing its interaction with importin α, which facilitates FOXK2's nuclear translocation and binding to the SLC7A11 promoter region. This, in turn, boosts SLC7A11 transcription, thereby inhibiting ferroptosis. The elevated OGT-FOXK2-SLC7A11 axis contributes to tumorigenesis and resistance to chemoradiotherapy in hepatocellular carcinoma (HCC). Our findings elucidate a ROS-induced oxidation-O-GlcNAcylation cascade that integrates ROS signaling, O-GlcNAcylation, FOXK2-mediated SLC7A11 transcription, and resistance to both ferroptosis and chemoradiotherapy.
2025-05-28 | PXD064117 | Pride
Project description:Purpose: 5-FU resistance is considered to be a possible reason for the failure of conventional drug treatment of colorectal cancer (CRC). Recently, salinomycin (SAL), as a selective inhibitor of cancer stem cells (CSCs), has been used to sensitize and attenuate a variety of solid tumor chemotherapy drugs. In our study, our goal was to combine SAL with 5-FU to explore whether increase the sensitivity of CRC to 5-FU and the molecular mechanism that involved in enhancing 5-FU sensitivity and promoting tumor cell chemotherapeutic death. Methods: ComboSyn software was used to study whether dual drug combinations synergistically promote each other and their dosage. CCK8, EdU and Annexin V/PI assays were used to study the cell proliferation and apoptosis of SW480 and HCT116 cells in response to SAL single-drug and dual-drug co-treatment. Cell cycle staining was used to assess cycle arrest. Wound healing and migration and invasion experiments were used to identify changes in migration and invasion capabilities under the influence of different drugs. Transcriptome sequencing is used to explore the molecular mechanisms of drugs. ROS fluorescence staining and MDA level measurement were used to confirm the changes in ferroptosis levels of SW480 and HCT116 cells after drug treatment. Nude xenograft mice were used to detect antitumor in vivo. Changes in the protein level expression of ferroptosis GPX4 and SLC7A11 were also determined in the treated cells.Results: SAL alone and combination of 5-FU were found to significantly increase cell mortality and apoptosis. At the same time, our results show that the blending of SAL and 5-FU not only inhibits the proliferation, migration, and invasion of CRC colorectal cancer cell lines in vivo and in vitro, but also promotes ferroptosis of CRC cell lines by downregulating the expression of GPX4 and SLC7A11. It may provide more and novel solutions and treatment perspectives for 5-FU or other drug-resistant chemotherapy strategies for CRC patients.Conclusions: SAL inhibiting colorectal cancer whose effect is achieved by reducing GPX4 and SLC7A11 protein levels to mediate ferroptosis activation in collaboration with 5-fluorouracil.
2025-06-21 | E-MTAB-15206 | biostudies-arrayexpress
Project description:We conducted a proteomic interactome analysis of well-known regulators of ferroptosis, ACSL4, LPCAT3, ALOX12, ALOX15, PEBP1, NCOA4, GCH1, FSP1, DHODH, SLC7A11, GCLC, GCLM, GSS, and GPX4. Take LPCAT3 as an example, we uncovered an opposing role of its binding protein CEPT1 in suppressing ferroptosis.
2024-10-17 | PXD035146 | Pride
Project description:We performed RNA sequencing (RNA-seq) on cervical tissues from 3 patients with SCC (IB stage, HPV16-positive) and 3 normal controls (HPV16-negative). Differential gene expression, functional enrichment, and protein-protein interaction (PPI) network analyses were conducted to screen key microRNAs (miRNAs) and target genes. Expression of miR-143-3p and SLC7A11 in SCC and normal control tissues was determined by quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemical staining, and Western blotting (WB). Furthermore, the effect of miR-143-3p mimics and inhibitors on cell proliferation and ferroptosis was evaluated via Cell Counting Kit (CCK)-8 and scratch assays, along with WB, while concurrently detecting ferroptosis-related biochemical markers. Finally, the role of miR-143-3p in epithelial-mesenchymal transition (EMT) of cervical cancer cells was evaluated by WB and immunofluorescence.
2026-07-31 | E-MTAB-17403 | biostudies-arrayexpress
Project description:Compared to the well-established roles of apoptosis in tumor suppression, the roles and regulatory mechanisms of ferroptosis, a non-apoptotic form of cell death, in tumor biology remain much less understood. BRCA1-associated protein 1 (BAP1) encodes a nuclear de-ubiquitinating (DUB) enzyme to reduce histone 2A ubiquitination (H2Aub) on chromatin, and is a tumor suppressor in several human cancers. Here, integrated transcriptomic, epigenomic, and cancer genomic analyses link BAP1 to metabolism-related biological processes, including oxidative stress response, and identify cystine transporter SLC7A11 as a BAP1-repressed target gene with high relevance to BAP1-mediated tumor suppression in human cancers. Functional studies reveal that BAP1, in a DUB-dependent manner, decreases H2Aub occupancy on the SLC7A11 promoter and represses SLC7A11 expression, and that BAP1 inhibits cystine uptake and promotes ferroptosis through repressing SLC7A11 expression. Finally, we show that BAP1 inhibits tumor development partly through SLC7A11, and that cancer-associated BAP1 mutants lose their abilities to repress SLC7A11 and to promote ferroptosis. Together, the results of our study show that BAP1 executes its tumor suppression function at least partly through its regulation of SLC7A11 and ferroptosis, and uncover a previously unappreciated mechanism coupling ferroptosis to tumor suppression.
2018-07-05 | GSE101987 | GEO
Project description:Ferroptosis is restrained by layered antioxidant defenses, yet whether glycolytic enzymes directly constitute ferroptosis-defense machinery remains unclear. Here we identify phosphoglycerate kinase 1 (PGK1) as a non-canonical suppressor of ferroptosis that functions independently of its glycolytic kinase activity. Across pan-cancer bulk and single-cell transcriptomes, glycolysis inversely associates with ferroptosis programs, with PGK1 emerging as a prognostic hub. PGK1 loss in multiple tumor models elicits hallmark ferroptotic features, elevates lipid peroxidation and labile iron, and suppresses xenograft growth, all of which are reversed by liproxstatin-1. Mechanistically, PGK1 physically binds the C-terminal tail of SLC7A11 (aa 471-501) and shields it from ubiquitin-proteasome degradation, thereby sustaining cystine-driven glutathione synthesis and redox homeostasis. This scaffolding role is preserved in a kinase-dead PGK1 mutant, establishing a strict separation between metabolic and ferroptosis-regulatory functions. Restoring SLC7A11 rescues PGK1-deficient tumor growth, whereas a rationally designed competing peptide SLC7A11471-501 (FP-01) disrupts the PGK1-SLC7A11 interface, depletes SLC7A11/GSH, triggers ferroptosis, and suppresses tumor progression in vivo. Collectively, the PGK1-SLC7A11 interaction represents a druggable ferroptosis vulnerability that enables selective ferroptosis induction while sparing essential glycolysis.
2026-07-12 | GSE317428 | GEO
Project description:Ferroptosis is restrained by layered antioxidant defenses, yet whether glycolytic enzymes directly constitute ferroptosis-defense machinery remains unclear. Here we identify phosphoglycerate kinase 1 (PGK1) as a non-canonical suppressor of ferroptosis that functions independently of its glycolytic kinase activity. Across pan-cancer bulk and single-cell transcriptomes, glycolysis inversely associates with ferroptosis programs, with PGK1 emerging as a prognostic hub. PGK1 loss in multiple tumor models elicits hallmark ferroptotic features, elevates lipid peroxidation and labile iron, and suppresses xenograft growth, all of which are reversed by liproxstatin-1. Mechanistically, PGK1 physically binds the C-terminal tail of SLC7A11 (aa 471-501) and shields it from ubiquitin-proteasome degradation, thereby sustaining cystine-driven glutathione synthesis and redox homeostasis. This scaffolding role is preserved in a kinase-dead PGK1 mutant, establishing a strict separation between metabolic and ferroptosis-regulatory functions. Restoring SLC7A11 rescues PGK1-deficient tumor growth, whereas a rationally designed competing peptide SLC7A11471-501 (FP-01) disrupts the PGK1-SLC7A11 interface, depletes SLC7A11/GSH, triggers ferroptosis, and suppresses tumor progression in vivo. Collectively, the PGK1-SLC7A11 interaction represents a druggable ferroptosis vulnerability that enables selective ferroptosis induction while sparing essential glycolysis.
2026-07-13 | GSE338472 | GEO
Project description:InactivatingSTK11/KEAP1 co-mutations are genomic drivers of primary resistance totherapies and worse outcome in KRAS-mutatedlung adenocarcinoma(LUAD), however the underlying mechanisms is still not understood.Here we provide a transcriptomic analysis of over 3800 “real-world” LUAD cases that concomitant loss of STK11 and KEAP1 in a KRAS-mutant tumorleads to significant upregulation of fatty acid metabolism, and redox signaling pathways with significantly high expression of ferroptosis evasion genes, SCD1 and SLC7A11. Global transcriptomics and kinase arrays demonstrate the role SCD1 in regulating AKT/GSK3β/NRF2 signaling mediated modulation of SLC7A11 and GSH metabolism. Furthermore, in a lipidomic assay, SCD1 knockout led to regulation of SFA-MUFA levels that promoted ferroptosis. SCD1 inhibition reverses the resistance to ferroptosis induction promoted by STK11/KEAP1 loss inmouse models. These data provide evidence that SCD1 protects ferroptosis induction and therapeutic targeting of this pathway is a promising translational strategy in KRAS mutant LUADs with concomitant loss ofSTK11 and KEAP1.
2025-02-07 | GSE262660 | GEO
Project description:Numerous neurological diseases involve neuroinflammation, a process in which immune cells, particularly microglia, contribute to neuronal death. Ferroptosis, a recently identified form of regulated cell death, is implicated in various diseases characterized by neuronal injury. Nicotinamide mononucleotide (NMN), a potent NAD+ precursor supplement, has been found to inhibit neuroinflammation and ferroptosis. However, the mechanisms of NMN in both ferroptosis and neuroinflammation remains unclear. The present study aimed to investigate the impact of NMN on neuroinflammation and the susceptibility of microglia to ferroptosis. Ferroptosis markers in microglia exposed to lipopolysaccharide (LPS) were analyzed using CCK8, flow cytometry, ELISA, and RT-qPCR. The effects of NMN on LPS-induced ferroptosis in microglia were evaluated through flow cytometry, western blotting, and immunofluorescence staining. RT-qPCR analysis assessed the inflammatory cytokine production of microglia subjected to ferrostatin-1-regulated ferroptosis. RNA sequencing elucidated the underlying mechanisms of NMN-associated microglia ferroptosis under LPS induction. In BV2 microglia, an inhibitor of Glutathione Peroxidase 4(GPX4), RSL3, was employed to suppress GPX4 expression. Intracerebroventricular injection of LPS was performed to evaluate neuroinflammation and microglia activation in vivo. LPS treatment resulted in decreased cell viability, accompanied by upregulation of ferroptosis markers SLC7A11 and GPX4, and elevated levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and total iron in a dose-dependent manner. NMN effectively rescued LPS-induced ferroptosis and improved cell viability in microglia. Co-administration of NMN and ferrostatin-1 significantly reduced proinflammatory cytokine production in microglia following the introduction of LPS stimuli. Mechanistically, NMN facilitated glutathione (GSH) production, and promoted resistance to lipid peroxidation in a GPX4-dependent manner, repressing cytokine transcription and protecting cells from ferroptosis. RNA sequencing elucidated the underlying mechanism of NMN-associated microglia ferroptosis under LPS induction. Furthermore, simultaneous injection of NMN ameliorated LPS-induced ferroptosis and neuroinflammation in mouse brains. The data from the present study indicated that NMN enhances GPX4-mediated ferroptosis defense against LPS-induced ferroptosis in microglia by recruiting GSH, thereby inhibiting neuroinflammation. Therefore, therapeutic approaches targeting ferroptosis in diseases using NMN should consider both its anti-ferroptosis and anti-inflammatory effects to achieve optimal outcomes, presenting promising strategies for treating neuroinflammation-related diseases or disorders.
2025-03-01 | GSE262303 | GEO