Affinage

GSDME

Gasdermin-E · UniProt O60443

Length
496 aa
Mass
54.6 kDa
Annotated
2026-06-10
100 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/9 claims corpus-supported (89%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GSDME (DFNA5) is a gasdermin-family pore-forming protein that converts apoptotic signaling into lytic, inflammatory cell death (pyroptosis/secondary necrosis) by permeabilizing the plasma membrane (PMID:28045099). Its canonical activation is caspase-3 cleavage after Asp270, which liberates an N-terminal fragment (GSDME-N) that targets the plasma membrane; cells expressing GSDME progress to secondary necrosis upon apoptotic stimulation, whereas GSDME-null cells disassemble into apoptotic bodies (PMID:28045099). The protein is bipartite, with the N-terminal domain executing membrane damage and the C-terminal domain masking and autoinhibiting this activity (PMID:21522185). At the membrane GSDME-N forms size-selective pores that govern the influx of macromolecules and accelerate cell lysis (PMID:34971436), and its membrane recruitment is mediated in part by flotillin-2 (PMID:39378585). This caspase-3/GSDME axis is engaged downstream of diverse apoptotic triggers, including targeted anticancer therapies acting through the mitochondrial intrinsic pathway (PMID:30061362) and caspase-8-dependent TNF Complex IIb signaling (PMID:36823174). GSDME can also be activated independently of cleavage: DNA damage drives PARP1/PARP5-mediated PARylation of full-length GSDME, relieving autoinhibition and coupling to lipid-ROS sensing to trigger oxidative oligomerization and membrane targeting (PMID:38997456). GSDME abundance and activation are controlled at multiple layers — transcriptionally by p53 (PMID:16897187, PMID:39215364), Sp1 (PMID:38238307), STAT3 (PMID:36807553) and ZEB1/2 (PMID:34901025), epigenetically through ALKBH4-regulated H3K4me3 (PMID:38902235); post-translationally by AMPK phosphorylation at Thr6 that blocks caspase-3 cleavage (PMID:37460805), C-domain palmitoylation by ZDHHC enzymes that modulates autoinhibition (PMID:32332857), and opposing ubiquitin-dependent turnover via CDC20 and stabilization by the deubiquitinase OTUD4 (PMID:36411454, PMID:37528490). Beyond pore formation, the GSDME-C fragment interacts with PDPK1 in macrophages to activate PI3K-AKT signaling and promote M2-like polarization (PMID:39496854). Loss-of-function and gain-of-function studies link GSDME to autosomal dominant hearing loss (DFNA5), where exon-8-skipped mutant protein produces a necrotic gain-of-function cell-death phenotype (PMID:15173223).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2004 Medium

    Established that disease-associated DFNA5 acts through a gain-of-function cytotoxic mechanism rather than haploinsufficiency, reframing how DFNA5 mutations cause hearing loss.

    Evidence Transfection of wild-type vs. exon-8-deleted mutant DFNA5 in mammalian cells with flow cytometry and microscopy

    PMID:15173223

    Open questions at the time
    • Molecular identity of the death-executing fragment not yet defined
    • Mechanism by which the mutant is constitutively active unresolved
  2. 2004 Medium

    First in vivo developmental role addressed: whether dfna5 functions in ear morphogenesis, linking it to ugdh-dependent matrix synthesis.

    Evidence Morpholino knockdown in zebrafish with ugdh in situ hybridization and hyaluronic acid detection

    PMID:14736743

    Open questions at the time
    • Connection between a pore-forming death protein and ugdh regulation mechanistically unexplained
    • Relationship to the later-defined pyroptotic function unclear
  3. 2006 High

    Answered how GSDME expression is induced in response to genotoxic stress, placing it downstream of p53 as a death effector.

    Evidence ChIP and reporter assays identifying a p53 site in intron 1, validated in p53-knockout mice after irradiation

    PMID:16897187

    Open questions at the time
    • Did not define the post-transcriptional activation step
    • Effector mechanism of the induced protein not yet known
  4. 2011 Medium

    Defined the bipartite architecture, showing the N-terminal domain is the death-inducing module and the C-terminal domain is autoinhibitory.

    Evidence Domain transfection in HEK293T cells plus Dfna5-knockout mouse expression microarray

    PMID:21522185

    Open questions at the time
    • The physiological protease liberating the N-domain not identified
    • Membrane-permeabilization activity vs. apoptosis distinction unresolved
  5. 2017 High

    Identified the activating cleavage event, establishing GSDME as a caspase-3 substrate whose N-fragment drives secondary necrosis/pyroptosis.

    Evidence Cleavage-site mutagenesis (Asp270), knockout, and plasma-membrane targeting assays after apoptotic stimulation

    PMID:28045099

    Open questions at the time
    • Pore architecture and selectivity not characterized
    • Membrane recruitment partners unknown
  6. 2019 Medium

    Connected GSDME activation to clinically relevant apoptotic inputs—targeted therapies and Bnip3/TNF signaling—showing it converts drug- and cytokine-induced apoptosis into pyroptosis across tissues.

    Evidence Drug treatment, Bnip3/caspase manipulation, knockdowns, xenograft and cardiomyocyte/myotube models

    PMID:30061362 PMID:31862454

    Open questions at the time
    • Tissue-specific determinants of pyroptosis vs. apoptosis outcome unclear
    • Quantitative threshold of GSDME needed for lysis undefined
  7. 2021 Medium

    Characterized the pore biophysically, showing GSDME governs size-selective macromolecular passage and accelerates lysis during secondary necrosis.

    Evidence Size-fractionated dextran influx/efflux and SYTOX assays in GSDME-knockout cells

    PMID:34971436

    Open questions at the time
    • Structural pore stoichiometry not resolved
    • Single cell-line system
  8. 2021 Medium

    Expanded transcriptional control by showing EMT-driving ZEB1/2 directly activate GSDME, linking cell-state plasticity to pyroptotic competence.

    Evidence ChIP for ZEB1/2 promoter binding plus EMT induction/reversal and drug-treatment assays

    PMID:34901025

    Open questions at the time
    • Reversibility mechanism at chromatin not defined
    • Interplay with other transcription factors untested here
  9. 2020 Medium

    Revealed lipid-modification control of autoinhibition: ZDHHC-mediated palmitoylation of GSDME-C modulates pyroptotic activation.

    Evidence Palmitoylation assays, site mutagenesis, 2-BP inhibition and Co-IP with multiple ZDHHC enzymes

    PMID:32332857

    Open questions at the time
    • Precise effect of palmitoylation on N/C-domain interaction mechanistically incomplete
    • Which ZDHHC dominates in vivo unknown
  10. 2022 Medium

    Identified deubiquitination as a stabilizing layer, with OTUD4 raising GSDME levels to enhance radiosensitivity.

    Evidence Co-IP/mass spectrometry, functional in vitro/in vivo assays and patient IHC in nasopharyngeal carcinoma

    PMID:36411454

    Open questions at the time
    • Ubiquitin linkage type and sites not mapped
    • Opposing ligase at the time unidentified
  11. 2023 Medium

    Established opposing ubiquitin-dependent turnover, with CDC20 driving degron-dependent GSDME degradation to gate the apoptosis-to-pyroptosis transition.

    Evidence Cycloheximide chase, ubiquitination assays, Co-IP and syngeneic mouse models

    PMID:37528490

    Open questions at the time
    • Degron sequence detail limited
    • Regulation of CDC20-GSDME by cell-cycle state unexplored
  12. 2023 High

    Discovered metabolic phospho-regulation: GlcNAc-6P/AMPK phosphorylation of GSDME at Thr6 blocks caspase-3 cleavage, repressing pyroptosis.

    Evidence Metabolite-AMPK binding, AMPK-knockout and GSDME T6E/T6A knock-in mice with in vitro cleavage assays

    PMID:37460805

    Open questions at the time
    • Structural basis of how Thr6 phosphorylation occludes the Asp270 site unresolved
    • Generality across cell types untested
  13. 2023 Medium

    Extended transcriptional and functional reach to macrophage biology and atherosclerosis via STAT3-driven GSDME expression.

    Evidence GSDME/ApoE double-knockout mice, ox-LDL macrophage treatment and STAT3 functional analysis

    PMID:36807553

    Open questions at the time
    • Direct STAT3 promoter binding not shown here
    • Cell-autonomy vs. systemic effects partly conflated
  14. 2024 High

    Defined a cleavage-independent activation route, showing PARP1/PARP5 PARylation of full-length GSDME relieves autoinhibition and couples to lipid-ROS sensing for oligomerization.

    Evidence UV-C irradiation with PARP1/PARP5 inhibition/knockout, PARylation, lipid-ROS, oligomerization and membrane-targeting assays

    PMID:38997456

    Open questions at the time
    • PARylation site(s) on GSDME not mapped
    • How lipid ROS is structurally sensed unresolved
  15. 2024 High

    Identified flotillin-2 as the membrane-recruitment partner for GSDME-N and extended pore function to platelet hyperactivity and thrombosis.

    Evidence Human and GSDME-knockout mouse platelets, cleavage and pore assays, Co-IP and thrombosis models

    PMID:39378585

    Open questions at the time
    • Structural basis of flotillin-2/GSDME-N interaction unknown
    • Whether flotillin-2 recruitment generalizes to other cell types untested
  16. 2024 Medium

    Revealed a non-pore-forming signaling role: GSDME-C binds PDPK1 to activate PI3K-AKT and promote M2-like macrophage polarization.

    Evidence Co-IP, Eliprodil inhibition, single-cell sequencing and in vivo HCC models

    PMID:39496854

    Open questions at the time
    • Structural interface of GSDME-C/PDPK1 undefined
    • Balance between pyroptotic and signaling roles in vivo unclear
  17. 2024 Medium

    Added further regulatory and downstream nodes: Sp1 promoter activation, ALKBH4-controlled H3K4me3 repression, p53/ULK1 control, and a GSDME-dependent Drp1-R114 citrullination/mitophagy axis.

    Evidence ChIP/reporter assays, ALKBH4 and ULK1 manipulation, GSDME-knockout/reintroduction and Drp1-R114 mutagenesis across cancer and MASH models

    PMID:38238307 PMID:38902235 PMID:39009654 PMID:39215364

    Open questions at the time
    • Mechanism linking GSDME to Drp1 citrullination not fully defined
    • Integration of these regulators into a single hierarchy untested
  18. 2024 Medium

    Showed GSDME is the lytic effector arm of cytotoxic-lymphocyte/IFNγ antitumor immunity, with STAT1-GSDME circuitry required for HDAC-inhibitor efficacy.

    Evidence ChIP-seq, single-cell multiomics, genetic GSDME/STAT1 knockout and orthotopic HCC models

    PMID:39486886

    Open questions at the time
    • Which protease (GZMB vs caspase-3) dominates cleavage in this setting partly open
    • Direct STAT1 regulation of GSDME locus vs. immune-cell recruitment effects entangled

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple activation inputs (caspase-3 cleavage, PARylation, lipid-ROS sensing) and antagonistic post-translational marks (Thr6 phosphorylation, palmitoylation, ubiquitination, O-glycosylation) are integrated at the structural level to set the threshold between apoptosis and pyroptosis remains unresolved.
  • No high-resolution structure of activated GSDME-N pore or of the autoinhibited full-length protein in the corpus
  • PARylation and modification sites not jointly mapped
  • Quantitative model of competing modifications absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0008289 lipid binding 1 GO:0140313 molecular sequestering activity 1
Localization
GO:0005886 plasma membrane 4 GO:0005634 nucleus 1
Pathway
R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 3
Partners
AMPKCDC20FLOT2OTUD4PARP1PDPK1ZDHHC2ZDHHC7

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 Caspase-3 cleaves GSDME (DFNA5) after Asp270 to generate a necrotic N-terminal fragment (GSDME-N) that targets the plasma membrane to induce secondary necrosis/pyroptosis. Cells expressing GSDME progress to secondary necrosis upon apoptotic stimulation, while GSDME-deleted cells disassemble into apoptotic bodies instead. Cell-based cleavage assays, GSDME deletion/knockout, apoptotic stimulation (etoposide, VSV infection), plasma membrane targeting assays Nature communications High 28045099
2004 Mutant DFNA5 (exon 8 skipped) transfected into HEK293T and COS-1 cells causes approximately doubled post-transfection cell death attributable to necrotic (not apoptotic) events, supporting a gain-of-function mechanism for DFNA5-associated hearing loss. Transfection of GFP-tagged wild-type vs. mutant DFNA5 in mammalian cell lines, flow cytometry, fluorescence microscopy Journal of medical genetics Medium 15173223
2011 GSDME is composed of two domains separated by a hinge region: the N-terminal domain induces apoptosis when transfected in HEK293T cells, while the C-terminal domain masks and regulates this apoptosis-inducing capability. Knockout mice microarray analysis further supported involvement of GSDME in apoptosis-related pathways. Domain transfection in HEK293T cells, gene expression microarray using Dfna5 knockout mice European journal of human genetics : EJHG Medium 21522185
2006 DFNA5 gene expression is strongly induced by p53 (both exogenous and endogenous). Chromatin immunoprecipitation identified a p53-binding sequence in intron 1 of DFNA5, and a reporter assay confirmed p53-dependent transcriptional activity at this site. Ectopic DFNA5 enhanced etoposide-induced cell death in a p53-dependent manner. Chromatin immunoprecipitation (ChIP), reporter gene assay, p53 overexpression/knockout systems, gamma-ray irradiation in p53+/+ vs p53-/- mice Journal of human genetics High 16897187
2015 Mutant DFNA5 (exon 8 deleted) induces programmed cell death through MAPK-related pathways in human cell lines (MAP kinase activity upregulated; inhibition partially attenuated cell death) and through mitochondrial pathways in yeast (cytochrome c oxidase genes upregulated). Both models showed downregulation of protein sorting/folding mechanisms. Microarray gene expression analysis in HEK293T cells and S. cerevisiae, MAPK pathway inhibition assays Frontiers in cellular neuroscience Medium 26236191
2004 Morpholino knockdown of dfna5 in zebrafish disrupts ugdh (UDP-glucose dehydrogenase) expression in the developing ear and pharyngeal arches, resulting in strongly reduced hyaluronic acid levels in developing semicircular canals and disorganized ear/cartilage development. Morpholino antisense knockdown in zebrafish, in situ hybridization for ugdh, HA detection in developing semicircular canals Development (Cambridge, England) Medium 14736743
2020 GSDME-C domain is palmitoylated during chemotherapy-induced pyroptosis. 2-Bromopalmitate (2-BP) inhibits GSDME-C palmitoylation and chemotherapy-induced pyroptosis. Mutation of palmitoylation sites on GSDME diminishes pyroptosis. 2-BP treatment increased the interaction between GSDME-C and GSDME-N. ZDHHC-2, 7, 11, and 15 interact with and palmitoylate GSDME. Palmitoylation assays, 2-BP pharmacological inhibition, palmitoylation site mutagenesis, co-immunoprecipitation with ZDHHC proteins, GSDME knockdown Cell death & disease Medium 32332857
2022 OTUD4 deubiquitinates and stabilizes GSDME protein, enhancing radiosensitivity in nasopharyngeal carcinoma by promoting GSDME-dependent pyroptosis. OTUD4 expression correlates with GSDME levels in NPC biopsies. Immunoprecipitation assays, mass spectrometry, in vitro and in vivo functional assays, immunohistochemistry Journal of experimental & clinical cancer research : CR Medium 36411454
2023 CDC20, an E3 ubiquitin ligase component, targets GSDME for ubiquitination-mediated proteolysis in a degron-dependent manner, negatively regulating pyroptosis. Knockdown of CDC20 increases GSDME abundance and promotes transition from apoptosis to pyroptosis. Cycloheximide chase assay, immunoprecipitation, ubiquitination assay, RNA sequencing, qRT-PCR, western blotting, syngeneic mouse models Experimental hematology & oncology Medium 37528490
2023 Mannose metabolism increases N-acetylglucosamine-6-phosphate (GlcNAc-6P), which binds AMPK and facilitates AMPK phosphorylation by LKB1. Activated AMPK phosphorylates GSDME at Thr6, blocking caspase-3-induced GSDME cleavage and thereby repressing pyroptosis. This was confirmed in AMPK knockout and GSDME-T6E/T6A knock-in mice. Metabolite-AMPK binding assays, AMPK knockout mice, GSDME knock-in mice (T6E and T6A), in vitro cleavage assays, patient sample validation Cell research High 37460805
2024 Full-length (FL) GSDME can execute pyroptosis independent of proteolytic cleavage. UV-C-induced DNA damage activates nuclear PARP1, generating PAR polymers that activate PARP5 to PARylate GSDME, causing conformational change relieving autoinhibition. UV-C also promotes cytochrome c-catalysed cardiolipin peroxidation, elevating lipid ROS that is sensed by PARylated GSDME, leading to oxidative oligomerization and plasma membrane targeting of FL-GSDME. UV-C irradiation, PARP1/PARP5 inhibition and knockout, PARylation assays, lipid ROS detection, plasma membrane localization assays, oligomerization assays Nature cell biology High 38997456
2021 GSDME regulates pore size during apoptosis-driven secondary necrosis. In anti-Fas-treated cells, GSDME accelerates cell lysis and controls passage of size-dependent dextrans through the plasma membrane. GSDME loss hampers influx of fluorescent dextrans, while efflux occurs independently of GSDME. GSDME does not affect phosphatidylserine exposure. SYTOX Blue staining, dextran influx/efflux assays with various molecular weights, GSDME knockout L929sAhFas cells, flow cytometry Cellular and molecular life sciences : CMLS Medium 34971436
2024 Transcription factor Sp1 directly binds the GSDME promoter at the -36 to -28 site and promotes GSDME gene transcription. Sp1 knockdown or inhibition suppresses GSDME expression and reduces chemotherapy-induced pyroptosis. This regulation synergizes with STAT3 activity and antagonizes DNA methylation. Chromatin immunoprecipitation (ChIP), reporter assay, Sp1 knockdown, western blotting Cell death & disease Medium 38238307
2023 STAT3 directly correlates with and positively regulates GSDME expression in macrophages during atherosclerosis development. Ox-LDL induces GSDME expression and GSDME-mediated pyroptosis in macrophages. GSDME/ApoE dual knockout mice, ox-LDL treatment of macrophages, STAT3 correlation analysis and functional experiments, single-cell transcriptomics Nature communications Medium 36807553
2021 EMT-activating transcription factors ZEB1/2 directly bind the GSDME promoter and drive its transcriptional activation. EMT dictates reversible GSDME upregulation, and elevated GSDME undergoes proteolytic cleavage upon drug exposure to execute pyroptosis. Integrative bioinformatics, ChIP assay (ZEB1/2 binding to GSDME promoter), EMT induction/reversal experiments, drug treatment assays Frontiers in cell and developmental biology Medium 34901025
2024 ALKBH4 inhibits GSDME activation at the transcriptional level by suppressing H3K4me3 histone modification at the GSDME promoter region, thereby reducing 5-FU-induced pyroptosis in gastric cancer cells. ChIP assay for H3K4me3, ALKBH4 knockdown/overexpression, western blotting, colony formation, qRT-PCR Cell death & disease Medium 38902235
2024 The non-N-terminal fragment of GSDME (GSDME-C) within macrophages combines with PDPK1, activating the PI3K-AKT pathway and facilitating M2-like macrophage polarization. The small-molecule Eliprodil inhibited PDPK1 phosphorylation mediated by GSDME. Co-immunoprecipitation, flow cytometry, Eliprodil pharmacological inhibition, single-cell sequencing, in vivo HCC models Cellular & molecular immunology Medium 39496854
2024 In platelets, caspase-3 cleaves GSDME to release GSDME-N, which targets the platelet plasma membrane forming pores and facilitating platelet granule release, promoting hyperactivity and thrombotic potential. Flotillin-2 was identified as a GSDME-N interactor that recruits GSDME-N to the platelet membrane. Human platelets and GSDME knockout mouse platelets, caspase-3 cleavage assays, membrane pore assays, Co-IP identifying flotillin-2 interaction, thrombosis models Blood High 39378585
2024 p53 directly mediates GSDME transcription; dual-luciferase reporter assay and ChIP-qPCR confirmed p53 binding to the GSDME promoter. ULK1 depletion additionally upregulates GSDME cleavage via ROS/NLRP3 signaling, synergizing with p53-driven basal pyroptosis. Dual-luciferase reporter assay, ChIP-qPCR, CRISPR/Cas9 kinome screen, ULK1 knockout/overexpression, GSDME knockdown, flow cytometry, LDH assay Journal of experimental & clinical cancer research : CR Medium 39215364
2025 GSDME-mediated pyroptosis in HCC is controlled by a STAT1-GSDME pyroptotic circuitry: HDAC inhibitor CXD101 promotes H3K27 hyperacetylation of IFNγ-responsive genes, driving STAT1-dependent antitumor immunity; cytotoxic lymphocytes recruited produce IFNγ/GZMB that promotes GSDME cleavage, and GSDME deletion abolishes antitumor efficacy equivalently to STAT1 knockout. ChIP-sequencing, single-cell multiomics, genetic GSDME/STAT1 knockout, orthotopic mouse models, co-culture systems, chromatin accessibility analysis Gut Medium 39486886
2023 GALNT6 promotes GSDME degradation via O-glycosylation, reducing GSDME-mediated pyroptosis in pancreatic ductal adenocarcinoma cells. GALNT6 knockdown, western blotting, immunofluorescence, ELISA, scanning electron microscopy Frontiers in oncology Low 36925932
2024 GSDME deficiency in mice reduces citrullination at Arg-114 (R114) of dynamin-related protein 1 (Drp1), impairing Drp1 stability and its ability to redistribute to mitochondria for mitophagy; mutation of Drp1-R114 reduces its stability and promotes its degradation under MASH stress. RNA sequencing, quantitative proteomics, Drp1-R114 mutagenesis, GSDME knockout mice, myeloid-specific GSDME reintroduction, immunofluorescence Cell death and differentiation Medium 39009654
2019 Diverse targeted therapies (KRAS, EGFR, ALK inhibitors) engage the mitochondrial intrinsic apoptotic pathway, and the mobilized caspase-3 cleaves GSDME (encoded by DFNA5), which permeabilizes the cytoplasmic membrane and executes cell-lytic pyroptosis in addition to apoptosis in lung cancer cells. Immunoblot, phase-contrast imaging, scanning electron microscopy, flow cytometry, xenograft models, IHC of patient lung cancer tissues Clinical cancer research Medium 30061362
2019 In DOX-treated cardiomyocytes, Bnip3 upregulation promotes caspase-3 activation and subsequent GSDME cleavage, leading to pyroptotic cell death. Silencing Bnip3 blunts cardiomyocyte pyroptosis by reducing caspase-3 activation and GSDME cleavage. siRNA knockdown of GSDME and Bnip3, caspase-3 inhibition, western blot, LDH assay, flow cytometry, echocardiography in mouse model Life sciences Medium 31862454
2024 Cathepsin L degrades BMPR2 via the lysosomal pathway, reducing BMPR2 signaling and inducing caspase-3/GSDME-mediated endothelial cell pyroptosis to promote pulmonary hypertension. Restoring BMPR2 signaling prevents cathepsin L's pro-pyroptotic role. siRNA, lentiviral constructs, specific inhibitors, genetic cathepsin L ablation in PH rats, measurement of BMPR2/caspase-3/GSDME pathway in human PAH samples and experimental models Hypertension (Dallas, Tex. : 1979) Medium 39403807
2023 TNF-α triggers GSDME-mediated pyroptosis in myotubes through activating caspase-8 and caspase-3. TNF-α assembles TNF Complex IIb (rather than Complex IIa) to activate caspase-8, which then activates caspase-3 to cleave GSDME, leading to loss of myotubes. Caspase-8 and caspase-3 inhibitors, GSDME knockdown, comparison of TNF Complex IIa vs IIb assembly, western blotting, aged sarcopenia mouse model Cell death discovery Medium 36823174

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death. Nature communications 1249 28045099
2020 The caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer. Cell death discovery 537 33133646
2019 Chemotherapeutic paclitaxel and cisplatin differentially induce pyroptosis in A549 lung cancer cells via caspase-3/GSDME activation. Apoptosis : an international journal on programmed cell death 379 30710195
2020 Chemotherapy-induced pyroptosis is mediated by BAK/BAX-caspase-3-GSDME pathway and inhibited by 2-bromopalmitate. Cell death & disease 275 32332857
2017 GSDME mediates caspase-3-dependent pyroptosis in gastric cancer. Biochemical and biophysical research communications 258 29183726
2023 GSDME-mediated pyroptosis promotes the progression and associated inflammation of atherosclerosis. Nature communications 243 36807553
2020 HMGB1 released from GSDME-mediated pyroptotic epithelial cells participates in the tumorigenesis of colitis-associated colorectal cancer through the ERK1/2 pathway. Journal of hematology & oncology 234 33160389
2008 Aberrant promoter methylation and tumor suppressive activity of the DFNA5 gene in colorectal carcinoma. Oncogene 214 18223688
2018 Molecular Targeted Therapies Elicit Concurrent Apoptotic and GSDME-Dependent Pyroptotic Tumor Cell Death. Clinical cancer research : an official journal of the American Association for Cancer Research 211 30061362
2020 Miltirone induces cell death in hepatocellular carcinoma cell through GSDME-dependent pyroptosis. Acta pharmaceutica Sinica. B 208 32963939
2007 Identification of DFNA5 as a target of epigenetic inactivation in gastric cancer. Cancer science 207 17083569
2020 Metformin activates AMPK/SIRT1/NF-κB pathway and induces mitochondrial dysfunction to drive caspase3/GSDME-mediated cancer cell pyroptosis. Cell cycle (Georgetown, Tex.) 206 32286137
2021 Caspase 3/GSDME-dependent pyroptosis contributes to chemotherapy drug-induced nephrotoxicity. Cell death & disease 183 33589596
2021 GSDME-mediated pyroptosis promotes inflammation and fibrosis in obstructive nephropathy. Cell death and differentiation 175 33664482
2021 Natural product triptolide induces GSDME-mediated pyroptosis in head and neck cancer through suppressing mitochondrial hexokinase-ΙΙ. Journal of experimental & clinical cancer research : CR 173 34108030
2023 The pyroptotic role of Caspase-3/GSDME signalling pathway among various cancer: A Review. International journal of biological macromolecules 145 37196719
2022 HDAC11 promotes both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways causing pyroptosis via ERG in vascular endothelial cells. Cell death discovery 133 35279683
2019 Bnip3 mediates doxorubicin-induced cardiomyocyte pyroptosis via caspase-3/GSDME. Life sciences 132 31862454
2008 Methylation of the DFNA5 increases risk of lymph node metastasis in human breast cancer. Biochemical and biophysical research communications 126 18346456
2006 The potential role of DFNA5, a hearing impairment gene, in p53-mediated cellular response to DNA damage. Journal of human genetics 109 16897187
2001 DFNA5 (ICERE-1) contributes to acquired etoposide resistance in melanoma cells. FEBS letters 109 11297734
2011 The DFNA5 gene, responsible for hearing loss and involved in cancer, encodes a novel apoptosis-inducing protein. European journal of human genetics : EJHG 108 21522185
2023 TNF-α contributes to sarcopenia through caspase-8/caspase-3/GSDME-mediated pyroptosis. Cell death discovery 93 36823174
2018 Large-scale analysis of DFNA5 methylation reveals its potential as biomarker for breast cancer. Clinical epigenetics 91 29682089
2023 The multifaceted roles of GSDME-mediated pyroptosis in cancer: therapeutic strategies and persisting obstacles. Cell death & disease 88 38104141
2023 Mannose antagonizes GSDME-mediated pyroptosis through AMPK activated by metabolite GlcNAc-6P. Cell research 87 37460805
2021 Dihydroartemisinin induces pyroptosis by promoting the AIM2/caspase-3/DFNA5 axis in breast cancer cells. Chemico-biological interactions 86 33689708
2022 Apoptin induces pyroptosis of colorectal cancer cells via the GSDME-dependent pathway. International journal of biological sciences 80 35002520
2004 A novel mutation identified in the DFNA5 gene in a Dutch family: a clinical and genetic evaluation. Audiology & neuro-otology 77 14676472
2003 A 3-nucleotide deletion in the polypyrimidine tract of intron 7 of the DFNA5 gene causes nonsyndromic hearing impairment in a Chinese family. Genomics 75 14559215
2020 GSDME and its role in cancer: From behind the scenes to the front of the stage. International journal of cancer 74 33186472
2022 Alantolactone induces concurrent apoptosis and GSDME-dependent pyroptosis of anaplastic thyroid cancer through ROS mitochondria-dependent caspase pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 73 36343549
2013 The expression and regulation of DFNA5 in human hepatocellular carcinoma DFNA5 in hepatocellular carcinoma. Molecular biology reports 73 24154762
1998 Characterization of a gene that is inversely correlated with estrogen receptor expression (ICERE-1) in breast carcinomas. European journal of biochemistry 71 9523727
2022 OTUD4-mediated GSDME deubiquitination enhances radiosensitivity in nasopharyngeal carcinoma by inducing pyroptosis. Journal of experimental & clinical cancer research : CR 69 36411454
2012 Methylation of the DFNA5 gene is frequently detected in colorectal cancer. Anticancer research 67 22493364
2012 DFNA5, a gene involved in hearing loss and cancer: a review. The Annals of otology, rhinology, and laryngology 64 22530481
2024 Full-length GSDME mediates pyroptosis independent from cleavage. Nature cell biology 63 38997456
2024 Mitochondria-targeted photodynamic therapy triggers GSDME-mediated pyroptosis and sensitizes anti-PD-1 therapy in colorectal cancer. Journal for immunotherapy of cancer 62 38429070
2004 The deafness gene dfna5 is crucial for ugdh expression and HA production in the developing ear in zebrafish. Development (Cambridge, England) 57 14736743
2005 Mice lacking Dfna5 show a diverging number of cochlear fourth row outer hair cells. Neurobiology of disease 52 16023581
2004 DFNA5: hearing impairment exon instead of hearing impairment gene? Journal of medical genetics 52 15173223
2015 The deafness gene DFNA5 induces programmed cell death through mitochondria and MAPK-related pathways. Frontiers in cellular neuroscience 50 26236191
2022 Deoxynivalenol induces caspase-3/GSDME-dependent pyroptosis and inflammation in mouse liver and HepaRG cells. Archives of toxicology 49 35925383
2024 CircPDIA3/miR-449a/XBP1 feedback loop curbs pyroptosis by inhibiting palmitoylation of the GSDME-C domain to induce chemoresistance of colorectal cancer. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 46 38861804
2018 Exonic mutations and exon skipping: Lessons learned from DFNA5. Human mutation 46 29266521
2022 CXCR4-targeted nanotoxins induce GSDME-dependent pyroptosis in head and neck squamous cell carcinoma. Journal of experimental & clinical cancer research : CR 45 35120582
2009 Evidence for a founder mutation causing DFNA5 hearing loss in East Asians. Journal of human genetics 45 19911014
2022 Nitidine chloride induces caspase 3/GSDME-dependent pyroptosis by inhibting PI3K/Akt pathway in lung cancer. Chinese medicine 41 36175965
2023 Inhibition of CDC20 potentiates anti-tumor immunity through facilitating GSDME-mediated pyroptosis in prostate cancer. Experimental hematology & oncology 37 37528490
2021 Mini-Review: GSDME-Mediated Pyroptosis in Diabetic Nephropathy. Frontiers in pharmacology 37 34867412
2024 Transcription factor Sp1 transcriptionally enhances GSDME expression for pyroptosis. Cell death & disease 36 38238307
2022 Lobaplatin Induces Pyroptosis in Cervical Cancer Cells via the Caspase-3/GSDME Pathway. Anti-cancer agents in medicinal chemistry 36 34666646
2025 Pharmacological activation of STAT1-GSDME pyroptotic circuitry reinforces epigenetic immunotherapy for hepatocellular carcinoma. Gut 34 39486886
2023 Promoting GSDME expression through DNA demethylation to increase chemosensitivity of breast cancer MCF-7 / Taxol cells. PloS one 34 36867605
2022 GSDME Increases Chemotherapeutic Drug Sensitivity by Inducing Pyroptosis in Retinoblastoma Cells. Oxidative medicine and cellular longevity 34 35480866
2023 Inhibition of PINK1-Mediated Mitophagy Contributes to Postoperative Cognitive Dysfunction through Activation of Caspase-3/GSDME-Dependent Pyroptosis. ACS chemical neuroscience 32 36946264
2022 Iridium(III) complexes entrapped in liposomes trigger mitochondria-mediated apoptosis and GSDME-mediated pyroptosis. Journal of inorganic biochemistry 32 35033830
2020 Methamphetamine induces GSDME-dependent cell death in hippocampal neuronal cells through the endoplasmic reticulum stress pathway. Brain research bulletin 32 32544512
2024 Synthetic lethality of combined ULK1 defection and p53 restoration induce pyroptosis by directly upregulating GSDME transcription and cleavage activation through ROS/NLRP3 signaling. Journal of experimental & clinical cancer research : CR 29 39215364
2023 SNAP25 ameliorates postoperative cognitive dysfunction by facilitating PINK1-dependent mitophagy and impeding caspase-3/GSDME-dependent pyroptosis. Experimental neurology 29 37295545
2024 Targeting GSDME-mediated macrophage polarization for enhanced antitumor immunity in hepatocellular carcinoma. Cellular & molecular immunology 28 39496854
2014 A DFNA5 mutation identified in Japanese families with autosomal dominant hereditary hearing loss. Annals of human genetics 28 24506266
2021 Cordyceps militaris extract induces apoptosis and pyroptosis via caspase-3/PARP/GSDME pathways in A549 cell line. Food science & nutrition 27 35035907
2015 IVS8+1 DelG, a Novel Splice Site Mutation Causing DFNA5 Deafness in a Chinese Family. Chinese medical journal 27 26365971
2022 DFNA5 regulates immune cells infiltration and exhaustion. Cancer cell international 26 35248047
2019 The deafness gene GSDME: its involvement in cell apoptosis, secondary necrosis, and cancers. Naunyn-Schmiedeberg's archives of pharmacology 26 31230091
2007 A novel DFNA5 mutation does not cause hearing loss in an Iranian family. Journal of human genetics 26 17427029
2022 Blocking Caspase-1/Gsdmd and Caspase-3/-8/Gsdme pyroptotic pathways rescues silicosis in mice. PLoS genetics 25 36459518
2024 GSDMD and GSDME synergy in the transition of acute kidney injury to chronic kidney disease. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 24 38244230
2024 GSDME promotes MASLD by regulating pyroptosis, Drp1 citrullination-dependent mitochondrial dynamic, and energy balance in intestine and liver. Cell death and differentiation 24 39009654
2023 Caspase-3/GSDME mediated pyroptosis: A potential pathway for sepsis. International immunopharmacology 24 37837715
2022 Campylobacter jejuni Cytolethal Distending Toxin Induces GSDME-Dependent Pyroptosis in Colonic Epithelial Cells. Frontiers in cellular and infection microbiology 23 35573789
2022 Germacrone induces caspase-3/GSDME activation and enhances ROS production, causing HepG2 pyroptosis. Experimental and therapeutic medicine 23 35747157
2002 Is DFNA5 a susceptibility gene for age-related hearing impairment? European journal of human genetics : EJHG 22 12461698
2025 Hypericin photoactivation induces triple-negative breast cancer cells pyroptosis by targeting the ROS/CALR/Caspase-3/GSDME pathway. Journal of advanced research 21 39870303
2024 Gambogic acid induces GSDME dependent pyroptotic signaling pathway via ROS/P53/Mitochondria/Caspase-3 in ovarian cancer cells. Biochemical pharmacology 21 39643123
2022 Liproxstatin‑1 induces cell cycle arrest, apoptosis, and caspase‑3/GSDME‑dependent secondary pyroptosis in K562 cells. International journal of oncology 21 36004469
2018 Further evidence for "gain-of-function" mechanism of DFNA5 related hearing loss. Scientific reports 21 29849037
2021 Plasma membrane perforation by GSDME during apoptosis-driven secondary necrosis. Cellular and molecular life sciences : CMLS 20 34971436
2007 In CEM cells the autosomal deafness gene dfna5 is regulated by glucocorticoids and forskolin. The Journal of steroid biochemistry and molecular biology 20 17616391
2024 ALKBH4 impedes 5-FU Sensitivity through suppressing GSDME induced pyroptosis in gastric cancer. Cell death & disease 19 38902235
2023 Salidroside ameliorates severe acute pancreatitis-induced cell injury and pyroptosis by inactivating Akt/NF-κB and caspase-3/GSDME pathways. Heliyon 19 36747537
2023 Endogenous HMGB1 regulates GSDME-mediated pyroptosis via ROS/ERK1/2/caspase-3/GSDME signaling in neuroblastoma. American journal of cancer research 19 36895972
2023 GSDME-dependent pyroptosis signaling pathway in diabetic nephropathy. Cell death discovery 18 37169767
2023 Antileukemic effect of venetoclax and hypomethylating agents via caspase-3/GSDME-mediated pyroptosis. Journal of translational medicine 18 37679782
2025 Clofarabine induces tumor cell apoptosis, GSDME-related pyroptosis, and CD8+ T-cell antitumor activity via the non-canonical P53/STING pathway. Journal for immunotherapy of cancer 17 39915005
2024 Pharmacological inhibition of cGAS ameliorates postoperative cognitive dysfunction by suppressing caspase-3/GSDME-dependent pyroptosis. Neurochemistry international 17 38843953
2024 GSDME-mediated pyroptosis promotes anti-tumor immunity of neoadjuvant chemotherapy in breast cancer. Cancer immunology, immunotherapy : CII 17 38954046
2023 Proteasomal inhibitors induce myeloma cell pyroptosis via the BAX/GSDME pathway. Acta pharmacologica Sinica 17 36807412
2022 PD-L1 Regulates Platelet Activation and Thrombosis via Caspase-3/GSDME Pathway. Frontiers in pharmacology 17 35784685
2024 Inhibiting apoptosis and GSDME-mediated pyroptosis attenuates hepatic injury in septic mice. Archives of biochemistry and biophysics 16 38408533
2021 Epithelial-Mesenchymal Transition Induces GSDME Transcriptional Activation for Inflammatory Pyroptosis. Frontiers in cell and developmental biology 16 34901025
2023 Knocking down GALNT6 promotes pyroptosis of pancreatic ductal adenocarcinoma cells through NF-κB/NLRP3/GSDMD and GSDME signaling pathway. Frontiers in oncology 14 36925932
2023 Characterization of GSDME in amphioxus provides insights into the functional evolution of GSDM-mediated pyroptosis. PLoS biology 14 37134086
2025 Pyroptosis-Inducing Platinum(IV) Prodrugs via GSDME Pathway for Chemoimmunotherapy and Metastasis Inhibition in Triple-Negative Breast Cancer. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 13 40432601
2025 Repurposing MDM2 inhibitor RG7388 for TP53-mutant NSCLC: a p53-independent pyroptotic mechanism via ROS/p-p38/NOXA/caspase-3/GSDME axis. Cell death & disease 13 40523886
2024 Cathepsin L Promotes Pulmonary Hypertension via BMPR2/GSDME-Mediated Pyroptosis. Hypertension (Dallas, Tex. : 1979) 13 39403807
2023 GSDME in Endothelial Cells: Inducing Vascular Inflammation and Atherosclerosis via Mitochondrial Damage and STING Pathway Activation. Biomedicines 13 37761020
2024 GSDME-mediated pyroptosis contributes to chemotherapy-induced platelet hyperactivity and thrombotic potential. Blood 12 39378585

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