Affinage

GSDME

Gasdermin-E · UniProt O60443

Length
496 aa
Mass
54.6 kDa
Annotated
2026-04-28
100 papers in source corpus 21 papers cited in narrative 21 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GSDME is a gasdermin-family pore-forming protein that serves as a molecular switch converting apoptosis into pyroptosis, with broad roles in innate immunity, chemosensitivity, and inflammatory cell death. Caspase-3 cleaves GSDME after Asp270 to release a cytotoxic N-terminal fragment (GSDME-N) that oligomerizes and forms size-selective pores in the plasma membrane, executing secondary necrosis/pyroptosis; in cells lacking GSDME, apoptosis instead proceeds to orderly disassembly into apoptotic bodies (PMID:28045099, PMID:34971436). GSDME-N also penetrates mitochondrial membranes to trigger cytochrome c release and amplify caspase-3 activation in a feed-forward loop (PMID:36807412), and full-length GSDME can execute pyroptosis independently of cleavage through PARP1/PARP5-mediated PARylation coupled with lipid ROS-driven oxidative oligomerization (PMID:38997456). GSDME activity is regulated at multiple levels: transcriptionally by p53, Sp1, ZEB1/2, STAT1, and STAT3 (PMID:16897187, PMID:38238307, PMID:34901025, PMID:39486886); post-translationally by inhibitory AMPK phosphorylation at Thr6 (PMID:37460805), CDC20-mediated ubiquitin-dependent degradation opposed by OTUD4 deubiquitination (PMID:37528490, PMID:36411454), and ZDHHC-catalyzed palmitoylation of the autoinhibitory C-terminal domain that relieves intramolecular suppression (PMID:32332857, PMID:38861804).

Mechanistic history

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

    The first indication that GSDME harbors intrinsic cytotoxic capacity came from showing that a disease-linked truncation mutant (exon-8 skip) induces necrotic cell death in a gain-of-function manner, whereas the full-length protein is autoinhibited.

    Evidence Transfection of GFP-tagged wild-type versus exon-8-skipped GSDME in HEK293T/COS-1 cells with flow cytometry and microscopy readouts

    PMID:15173223

    Open questions at the time
    • Mechanism of autoinhibition by C-terminal domain not yet defined
    • No identification of the cleavage site or activating protease
  2. 2006 High

    Establishing that p53 directly transactivates GSDME via an intronic response element linked GSDME expression to the DNA damage response and explained why genotoxic stress potentiates GSDME-dependent cell death.

    Evidence ChIP for p53 binding to intron 1, promoter-reporter assay, p53+/+ versus p53−/− mouse colon, etoposide treatment

    PMID:16897187

    Open questions at the time
    • Whether other transcription factors cooperate with p53 at the GSDME locus was unknown
    • The downstream effector mechanism (pore formation) had not been identified
  3. 2017 High

    The central activating mechanism was resolved: caspase-3 cleaves GSDME after Asp270 to liberate a pore-forming N-terminal fragment that targets the plasma membrane and switches apoptosis to pyroptosis — establishing GSDME as a gasdermin-family executioner.

    Evidence In vitro caspase cleavage, D270A mutagenesis, GSDME-KO cells showing apoptotic body formation instead of pyroptosis, plasma membrane targeting assay

    PMID:28045099

    Open questions at the time
    • Whether caspases other than caspase-3 can activate GSDME
    • Pore structure and stoichiometry undefined
    • Role of the C-terminal domain in autoinhibition not mechanistically dissected
  4. 2020 High

    Post-translational palmitoylation of the GSDME C-terminal domain by ZDHHC-family enzymes was shown to relieve autoinhibition by weakening the GSDME-C/GSDME-N intramolecular interaction, thereby licensing pyroptosis upon cleavage.

    Evidence Palmitoylation assay, 2-bromopalmitate inhibitor treatment, Co-IP of GSDME-C with GSDME-N, mutagenesis of palmitoylation sites

    PMID:32332857

    Open questions at the time
    • Identity of which specific palmitoylation sites are critical was incompletely resolved
    • Whether palmitoylation affects membrane targeting of GSDME-N directly
  5. 2020 High

    In inflammasome contexts lacking caspase-1/11, an alternative route to GSDME activation was identified: ASC-dependent caspase-8 cleaves GSDME to execute 'incomplete pyroptosis' with IL-1α but not IL-1β release, broadening the upstream activators of GSDME.

    Evidence Caspase-1/11 double-KO macrophages, ASC knockdown, caspase-8 inhibitor, GSDME knockdown, cytokine ELISA

    PMID:32361594

    Open questions at the time
    • Whether granzyme B can also directly cleave GSDME independent of caspase-3 in vivo
    • Structural basis for differential cytokine trapping
  6. 2021 Medium

    Characterization of GSDME pore selectivity showed that membrane permeabilization is size-dependent, accelerating lysis and molecular influx in a graded manner, while phosphatidylserine exposure is GSDME-independent — separating pore formation from apoptotic signaling.

    Evidence GSDME-KO L929 cells, dextran influx assays with graded molecular weight probes, SYTOX Blue, annexin V

    PMID:34971436

    Open questions at the time
    • Pore diameter and stoichiometry not structurally resolved
    • Single cell line used
  7. 2021 Medium

    EMT transcription factors ZEB1/ZEB2 were identified as direct transcriptional activators of GSDME, linking epithelial-mesenchymal transition status to pyroptotic competence across cancer types.

    Evidence ChIP for ZEB1/ZEB2 at GSDME promoter, ZEB1/2 knockdown, EMT induction/reversion models

    PMID:34901025

    Open questions at the time
    • Single-lab finding without independent replication
    • Whether ZEB-driven GSDME upregulation occurs in normal developmental EMT
  8. 2022 High

    GSDME protein stability was shown to be controlled by OTUD4-mediated deubiquitination, which stabilizes GSDME and enhances caspase-3-dependent pyroptosis — revealing ubiquitin-dependent turnover as a regulatory axis.

    Evidence Reciprocal IP and mass spectrometry identifying OTUD4, ubiquitination assays, OTUD4 overexpression/knockdown, in vivo radiosensitivity in NPC models

    PMID:36411454

    Open questions at the time
    • Identity of the E3 ligase opposing OTUD4 was not defined in this study
    • Specific ubiquitin chain type on GSDME not characterized
  9. 2023 High

    CDC20 was identified as the E3 ligase component targeting GSDME for ubiquitin-dependent proteasomal degradation; CDC20 depletion shifts the apoptosis-pyroptosis balance by stabilizing GSDME protein.

    Evidence Ubiquitination assay, cycloheximide chase, CDC20 knockdown/overexpression, syngeneic murine tumor models

    PMID:37528490

    Open questions at the time
    • Whether CDC20 and OTUD4 compete at the same ubiquitin sites on GSDME
    • Degron motif on GSDME not fully mapped
  10. 2023 Medium

    A mitochondrial feed-forward loop was established: GSDME-N penetrates mitochondrial membranes to release cytochrome c, which activates caspase-9/3 to generate more GSDME-N, amplifying pyroptosis; BAX acts upstream to initiate this cascade.

    Evidence GSDME-N overexpression, mitochondrial fractionation, cytochrome c release assay, BAX overexpression, Bcl-2/BAX IP in multiple myeloma cells

    PMID:36807412

    Open questions at the time
    • Single-lab finding in one cancer type
    • Structural basis for GSDME-N insertion into mitochondrial versus plasma membranes unknown
  11. 2023 Medium

    Evolutionary conservation of the gasdermin pore mechanism was demonstrated through amphioxus GSDME, showing that distinct caspase cleavage sites generate functionally opposing N-terminal fragments — one pyroptotic and bactericidal, the other inhibitory — and that key residues are functionally conserved in human GSDME.

    Evidence Amphioxus caspase cleavage assay, membrane binding, bacterial killing assay, mutagenesis of conserved residues, in vivo infection model

    PMID:37134086

    Open questions at the time
    • Whether human GSDME produces an analogous inhibitory fragment
    • In vivo relevance of dual-fragment mechanism in mammals
  12. 2023 High

    AMPK-mediated phosphorylation at Thr6 was identified as a metabolically regulated brake on GSDME: mannose-derived GlcNAc-6P activates AMPK via LKB1, and pThr6-GSDME resists caspase-3 cleavage, directly linking cellular metabolism to pyroptotic susceptibility.

    Evidence AMPK-KO and GSDME T6E/T6A knock-in mice, metabolite binding assay, in vitro caspase-3 cleavage, clinical correlation

    PMID:37460805

    Open questions at the time
    • Whether other kinases also phosphorylate GSDME-N
    • Structural basis for how pThr6 blocks caspase-3 access to Asp270
  13. 2024 High

    A cleavage-independent activation route was discovered: UV-C-induced DNA damage activates PARP1, generating free PAR polymers that activate cytoplasmic PARP5 to PARylate full-length GSDME; concurrent lipid ROS from cardiolipin peroxidation drive oxidative oligomerization of PARylated GSDME, enabling pore formation without proteolytic processing.

    Evidence PARP1/5 inhibitors and knockdown, PAR polymer detection, GSDME PARylation assay, lipid ROS measurement, cardiolipin peroxidation assay, confocal membrane targeting

    PMID:38997456

    Open questions at the time
    • Whether PARylation-dependent activation occurs under physiological (non-UV-C) stresses
    • Structural details of PARylated GSDME oligomer
    • Whether other gasdermins share this non-canonical activation route
  14. 2024 High

    Sp1 was identified as a direct transcriptional activator binding the GSDME proximal promoter (−36 to −28), synergizing with STAT3 and antagonized by promoter DNA methylation — integrating transcriptional and epigenetic control of GSDME expression.

    Evidence ChIP for Sp1 at GSDME promoter, luciferase reporter, Sp1 knockdown/inhibition, chemotherapy rescue experiments

    PMID:38238307

    Open questions at the time
    • Relative contribution of Sp1 versus p53 and ZEB1/2 in different cell types unresolved
    • Mechanism of DNA methylation–Sp1 interplay not fully dissected
  15. 2024 High

    In a non-canonical cell biology context, GSDME-N in platelets is recruited to the plasma membrane by flotillin-2, forming pores that drive granule release and platelet hyperactivation during chemotherapy — extending GSDME function beyond classical pyroptosis to hemostasis.

    Evidence GSDME-KO mice, Co-IP identifying flotillin-2, caspase-3 cleavage assay, platelet activation assays, cisplatin murine model

    PMID:39378585

    Open questions at the time
    • Whether flotillin-2 is required for GSDME-N membrane targeting in nucleated cells
    • In vivo thrombotic consequences beyond the cisplatin model
  16. 2024 High

    STAT1 was shown to drive GSDME transcription downstream of IFNγ, linking adaptive immune signaling (cytotoxic lymphocyte granzyme B/caspase-3) to tumor cell pyroptosis and establishing a self-reinforcing STAT1–GSDME circuit required for immunotherapy efficacy.

    Evidence GSDME-KO and STAT1-KO, ChIP-seq, single-cell multiomics, HDAC inhibitor + anti-PD1 in orthotopic HCC models

    PMID:39486886

    Open questions at the time
    • Whether STAT1 and STAT3 compete or cooperate at the GSDME locus under different cytokine contexts
    • Mechanism by which pyroptosis feeds back to amplify STAT1 signaling
  17. 2024 High

    circPDIA3 was shown to directly bind the GSDME-C domain and block its palmitoylation by ZDHHC3/17, strengthening autoinhibition and suppressing pyroptosis — revealing circular RNA as a post-translational modulator of gasdermin activation.

    Evidence RIP, RNA pulldown, Co-IP, palmitoylation assay, ZDHHC3/17 knockdown, PDX models in colorectal cancer

    PMID:38861804

    Open questions at the time
    • Whether other circRNAs or RNAs regulate other gasdermin family members
    • Stoichiometry of circPDIA3–GSDME-C interaction
  18. 2024 Medium

    The GSDME C-terminal fragment was found to have a signaling function beyond autoinhibition: interaction with PDPK1 activates PI3K–AKT to drive M2-like macrophage polarization, suggesting GSDME cleavage products have immunomodulatory roles in the tumor microenvironment.

    Evidence Co-IP of GSDME-C with PDPK1, GSDME KO, single-cell sequencing, Eliprodil inhibitor treatment in HCC mouse models

    PMID:39496854

    Open questions at the time
    • Single-lab finding; PDPK1 interaction awaits independent confirmation
    • Whether GSDME-C reaches macrophages in trans or acts cell-autonomously

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the cryo-EM structure of the GSDME pore, the mechanism by which PARylation relieves autoinhibition at the structural level, whether the cleavage-independent activation pathway operates under physiological (non-UV-C) stimuli, and how the opposing ubiquitin ligase (CDC20) and deubiquitinase (OTUD4) activities are coordinated in different tissues.
  • No cryo-EM or high-resolution structure of GSDME pore available
  • PARylation sites on GSDME not mapped
  • Physiological relevance of cleavage-independent pathway beyond UV-C not tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0005198 structural molecule activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005739 mitochondrion 1 GO:0005829 cytosol 1
Pathway
R-HSA-5357801 Programmed Cell Death 4 R-HSA-168256 Immune System 3 R-HSA-162582 Signal Transduction 2 R-HSA-109582 Hemostasis 1
Partners
AMPKCASP3CDC20FLOT2OTUD4PARP1PDPK1

Evidence

Reading pass · 21 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 GSDME-N fragment that targets the plasma membrane and induces secondary necrosis/pyroptosis; cells lacking GSDME instead disassemble into apoptotic bodies. In vitro caspase cleavage assay, site-directed mutagenesis, GSDME knockout cells, plasma membrane targeting assay, flow cytometry Nature Communications High 28045099
2004 Mutant GSDME (exon-8-skipped truncation) acts via a gain-of-function mechanism to induce necrotic cell death when transfected into mammalian cells, whereas wild-type GSDME does not cause equivalent cell death. Transfection of GFP-tagged wild-type vs. mutant DFNA5 in HEK293T and COS-1 cells; flow cytometry and fluorescence microscopy for cell death quantification Journal of Medical Genetics Medium 15173223
2006 GSDME is a transcriptional target of p53; p53 binds a response element in intron 1 of the DFNA5 gene and drives its expression upon genotoxic stress, and ectopic GSDME enhances etoposide-induced cell death in a p53-dependent manner. Chromatin immunoprecipitation (ChIP), reporter gene assay, p53-null vs. wild-type mouse colon, ectopic expression with etoposide treatment Journal of Human Genetics High 16897187
2020 GSDME-C domain is palmitoylated during chemotherapy-induced pyroptosis; palmitoylation is catalyzed by ZDHHC-2, -7, -11, and -15; 2-bromopalmitate inhibits GSDME-C palmitoylation and promotes interaction between GSDME-C and GSDME-N, blocking pyroptosis; mutation of palmitoylation sites on GSDME also diminishes pyroptosis. Palmitoylation assay, site-directed mutagenesis of palmitoylation sites, 2-BP inhibitor treatment, Co-IP between GSDME-C and GSDME-N, GSDME knockdown Cell Death & Disease High 32332857
2020 STAT3 directly correlates with and positively regulates GSDME expression in macrophages during atherosclerosis. ChIP/promoter analysis, STAT3 knockdown, GSDME-/-/ApoE-/- double-knockout mouse model, ox-LDL treatment of macrophages Nature Communications Medium 36807553
2022 OTUD4 (ovarian tumor family deubiquitinase 4) deubiquitinates and stabilizes GSDME, enhancing NPC radiosensitivity by promoting caspase-3-mediated GSDME cleavage and pyroptosis; low GSDME expression confers radioresistance. Immunoprecipitation, mass spectrometry, ubiquitination assay, OTUD4 overexpression/knockdown, in vitro and in vivo radiosensitivity assays Journal of Experimental & Clinical Cancer Research High 36411454
2023 CDC20 (E3 ligase component) targets GSDME for ubiquitination-mediated proteasomal degradation in a degron-dependent manner; CDC20 knockdown increases GSDME abundance and switches cell death from apoptosis to pyroptosis. Ubiquitination assay, immunoprecipitation, cycloheximide chase, CDC20 knockdown/overexpression, syngeneic murine models Experimental Hematology & Oncology High 37528490
2023 Mannose metabolism generates the metabolite GlcNAc-6P which binds AMPK and facilitates its phosphorylation by LKB1; activated AMPK then phosphorylates GSDME at Thr6, blocking caspase-3-induced cleavage and thereby suppressing pyroptosis. AMPK knockout and GSDME knock-in (T6E and T6A) mice, metabolite binding assay, AMPK phosphorylation assay, in vitro caspase-3 cleavage assay, patient clinical data Cell Research High 37460805
2024 Full-length GSDME (without proteolytic cleavage) can execute pyroptosis via a cleavage-independent mechanism: intense UV-C-induced DNA damage activates PARP1 to generate PAR polymers, which are released to the cytoplasm and activate PARP5 to PARylate GSDME; PARylated GSDME undergoes conformational change relieving autoinhibition; concurrent cytochrome c-catalysed cardiolipin peroxidation generates lipid ROS sensed by PARylated GSDME, driving oxidative oligomerization and plasma membrane targeting of FL-GSDME. UV-C irradiation, PARP1/PARP5 inhibitors and knockdown, PAR polymer detection, GSDME PARylation assay, lipid ROS measurement, cardiolipin peroxidation assay, confocal membrane targeting, pyroptosis readouts Nature Cell Biology High 38997456
2024 Sp1 (Specificity Protein 1) transcription factor directly binds the GSDME promoter at the -36 to -28 site and promotes GSDME gene transcription; this effect synergizes with STAT3 activity and is antagonized by DNA methylation. ChIP assay, promoter luciferase reporter assay, Sp1 knockdown/inhibition, rescue experiments with chemotherapy drugs Cell Death & Disease High 38238307
2021 EMT-activating transcription factors ZEB1 and ZEB2 directly bind the GSDME promoter to drive its transcriptional activation; GSDME levels positively correlate with EMT gene signatures across cancers and can be reversed when EMT is reverted. ChIP assay, ZEB1/2 knockdown, EMT induction/reversion models, bioinformatics correlation analysis Frontiers in Cell and Developmental Biology Medium 34901025
2024 circPDIA3 directly binds the GSDME-C domain and blocks its palmitoylation by ZDHHC3 and ZDHHC17, thereby enhancing the autoinhibitory effect of GSDME-C on GSDME-N and suppressing pyroptosis to promote chemoresistance in colorectal cancer. RIP, RNA pulldown, Co-IP, palmitoylation assay, ZDHHC3/17 knockdown, in vivo PDX models Drug Resistance Updates High 38861804
2023 GSDME-N fragment overexpressed in multiple myeloma cells can penetrate mitochondrial membranes and trigger cytochrome c release, activating caspase-3/9, establishing a forward amplification loop; BAX acts upstream to promote GSDME-dependent pyroptosis via the mitochondrial pathway. GSDME-N overexpression, cytochrome c release assay, mitochondrial fractionation, BAX overexpression, Bcl-2/BAX interaction by IP, GSDME KO rescue Acta Pharmacologica Sinica Medium 36807412
2024 In platelets, caspase-3 cleaves GSDME to release GSDME-N; flotillin-2 (a scaffold protein) interacts with GSDME-N and recruits it to the platelet plasma membrane, forming pores that facilitate granule release and platelet hyperactivity. GSDME-knockout mice, Co-IP identifying flotillin-2 as GSDME-N interactor, caspase-3 cleavage assay, platelet activation assays, cisplatin-treated murine model Blood High 39378585
2021 GSDME-mediated plasma membrane permeabilization during secondary necrosis is size-selective: GSDME accelerates cell lysis (SYTOX Blue influx) and mediates molecular-weight-dependent dextran influx, but phosphatidylserine exposure on the plasma membrane is independent of GSDME. GSDME KO L929sAhFas cells, dextran influx/efflux assay with different molecular weight probes, SYTOX Blue staining, annexin V staining Cellular and Molecular Life Sciences Medium 34971436
2024 The non-N-terminal fragment of GSDME within macrophages interacts with PDPK1, activating the PI3K-AKT pathway to facilitate M2-like macrophage polarization; inhibition of PDPK1 (by Eliprodil) blocks this GSDME-driven immunosuppressive effect. Co-IP (GSDME-C with PDPK1), flow cytometry (M2 macrophage proportion), GSDME KO in nontumor cells, single-cell sequencing, Eliprodil treatment in HCC mouse models Cellular & Molecular Immunology Medium 39496854
2026 ALKBH4 inhibits GSDME expression at the transcriptional level by reducing H3K4me3 histone modification at the GSDME promoter region, thereby suppressing GSDME-mediated pyroptosis and decreasing sensitivity to 5-FU in gastric cancer. ChIP for H3K4me3, ALKBH4 knockdown/overexpression, GSDME promoter activity assay, 5-FU sensitivity assay Cell Death & Disease Medium 38902235
2020 In caspase-1/11-deficient macrophages, NLRP3 inflammasome activation drives caspase-8 activation through ASC, which then cleaves GSDME to induce an 'incomplete pyroptosis' characterized by IL-1α but not IL-1β release (unprocessed pro-IL-1β is retained inside the pyroptotic cell in a molecular complex). Caspase-1/11 double-KO macrophages, ASC knockdown, caspase-8 inhibitor, GSDME knockdown, IL-1α/IL-1β ELISA, VX765 (caspase-1 pharmacological inhibitor) iScience High 32361594
2023 Amphioxus GSDME (BbGSDME) is cleaved by distinct caspase homologs to yield functionally distinct N-terminal fragments (N253 and N304): N253 binds cell membrane, triggers pyroptosis, and inhibits bacterial growth; N304 negatively regulates N253-mediated cell death; evolutionarily conserved amino acids are important for both BbGSDME and human GSDME function. Caspase cleavage assay, membrane binding assay, bacterial growth inhibition assay, mutational analysis of conserved residues, amphioxus in vivo infection model PLoS Biology Medium 37134086
2024 In a STAT1-dependent manner, IFNγ-induced STAT1 activation drives GSDME expression; cytotoxic lymphocyte-derived granzyme B or caspase-3 then cleaves GSDME to trigger pyroptosis; GSDME deletion abolishes the antitumor efficacy of HDAC inhibitor + anti-PD1 combination, demonstrating a self-reinforcing STAT1-GSDME pyroptotic circuitry. GSDME knockout (genetic), STAT1 knockout (genetic), chromatin immunoprecipitation-seq, single-cell multiomics, HDAC inhibitor treatment, co-culture systems, orthotopic HCC mouse models Gut High 39486886
2023 GZMB (granzyme B) cleaves caspase-3 to activate GSDME-mediated pyroptosis in RA synovial fibroblasts; GZMB silencing reduces GSDME cleavage and pyroptosis markers (LDH, IL-1β, IL-18). GZMB siRNA knockdown in HFLS-RA and MH7A cells, Western blot for caspase-3 and GSDME cleavage, LDH assay, ELISA Molecular Immunology Medium 37531918

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 1232 28045099
2020 The caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer. Cell death discovery 523 33133646
2019 Cleavage of GSDME by caspase-3 determines lobaplatin-induced pyroptosis in colon cancer cells. Cell death & disease 412 30804337
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 374 30710195
1998 Nonsyndromic hearing impairment is associated with a mutation in DFNA5. Nature genetics 320 9771715
2020 Chemotherapy-induced pyroptosis is mediated by BAK/BAX-caspase-3-GSDME pathway and inhibited by 2-bromopalmitate. Cell death & disease 271 32332857
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 229 33160389
2023 GSDME-mediated pyroptosis promotes the progression and associated inflammation of atherosclerosis. Nature communications 219 36807553
2008 Aberrant promoter methylation and tumor suppressive activity of the DFNA5 gene in colorectal carcinoma. Oncogene 210 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 208 30061362
2020 Miltirone induces cell death in hepatocellular carcinoma cell through GSDME-dependent pyroptosis. Acta pharmaceutica Sinica. B 205 32963939
2020 Metformin activates AMPK/SIRT1/NF-κB pathway and induces mitochondrial dysfunction to drive caspase3/GSDME-mediated cancer cell pyroptosis. Cell cycle (Georgetown, Tex.) 203 32286137
2007 Identification of DFNA5 as a target of epigenetic inactivation in gastric cancer. Cancer science 203 17083569
2021 Caspase 3/GSDME-dependent pyroptosis contributes to chemotherapy drug-induced nephrotoxicity. Cell death & disease 179 33589596
2021 GSDME-mediated pyroptosis promotes inflammation and fibrosis in obstructive nephropathy. Cell death and differentiation 168 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 168 34108030
2023 The pyroptotic role of Caspase-3/GSDME signalling pathway among various cancer: A Review. International journal of biological macromolecules 136 37196719
2019 Bnip3 mediates doxorubicin-induced cardiomyocyte pyroptosis via caspase-3/GSDME. Life sciences 130 31862454
2022 HDAC11 promotes both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways causing pyroptosis via ERG in vascular endothelial cells. Cell death discovery 127 35279683
2008 Methylation of the DFNA5 increases risk of lymph node metastasis in human breast cancer. Biochemical and biophysical research communications 124 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
2018 Large-scale analysis of DFNA5 methylation reveals its potential as biomarker for breast cancer. Clinical epigenetics 90 29682089
2023 TNF-α contributes to sarcopenia through caspase-8/caspase-3/GSDME-mediated pyroptosis. Cell death discovery 87 36823174
2021 Dihydroartemisinin induces pyroptosis by promoting the AIM2/caspase-3/DFNA5 axis in breast cancer cells. Chemico-biological interactions 85 33689708
2020 GSDME-Dependent Incomplete Pyroptosis Permits Selective IL-1α Release under Caspase-1 Inhibition. iScience 83 32361594
2023 Mannose antagonizes GSDME-mediated pyroptosis through AMPK activated by metabolite GlcNAc-6P. Cell research 82 37460805
2023 The multifaceted roles of GSDME-mediated pyroptosis in cancer: therapeutic strategies and persisting obstacles. Cell death & disease 80 38104141
2022 Apoptin induces pyroptosis of colorectal cancer cells via the GSDME-dependent pathway. International journal of biological sciences 79 35002520
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
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 71 36343549
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 65 22493364
2012 DFNA5, a gene involved in hearing loss and cancer: a review. The Annals of otology, rhinology, and laryngology 63 22530481
2024 Mitochondria-targeted photodynamic therapy triggers GSDME-mediated pyroptosis and sensitizes anti-PD-1 therapy in colorectal cancer. Journal for immunotherapy of cancer 57 38429070
2024 Full-length GSDME mediates pyroptosis independent from cleavage. Nature cell biology 56 38997456
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
2022 IL-6 Prevents Lung Macrophage Death and Lung Inflammation Injury by Inhibiting GSDME- and GSDMD-Mediated Pyroptosis during Pneumococcal Pneumosepsis. Microbiology spectrum 47 35297653
2021 Dihydroartemisinin mediating PKM2-caspase-8/3-GSDME axis for pyroptosis in esophageal squamous cell carcinoma. Chemico-biological interactions 46 34655567
2018 Exonic mutations and exon skipping: Lessons learned from DFNA5. Human mutation 46 29266521
2023 Baicalin inhibits influenza A (H1N1)-induced pyroptosis of lung alveolar epithelial cells via caspase-3/GSDME pathway. Journal of medical virology 45 37212338
2022 CXCR4-targeted nanotoxins induce GSDME-dependent pyroptosis in head and neck squamous cell carcinoma. Journal of experimental & clinical cancer research : CR 45 35120582
2022 Deoxynivalenol induces caspase-3/GSDME-dependent pyroptosis and inflammation in mouse liver and HepaRG cells. Archives of toxicology 44 35925383
2009 Evidence for a founder mutation causing DFNA5 hearing loss in East Asians. Journal of human genetics 44 19911014
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 43 38861804
2023 Degradation of Hexokinase 2 Blocks Glycolysis and Induces GSDME-Dependent Pyroptosis to Amplify Immunogenic Cell Death for Breast Cancer Therapy. Journal of medicinal chemistry 43 37376788
2022 Osthole Induces Apoptosis and Caspase-3/GSDME-Dependent Pyroptosis via NQO1-Mediated ROS Generation in HeLa Cells. Oxidative medicine and cellular longevity 42 35720178
2012 The splicing mutant of the human tumor suppressor protein DFNA5 induces programmed cell death when expressed in the yeast Saccharomyces cerevisiae. Frontiers in oncology 40 22848872
2003 A yeast model for the study of human DFNA5, a gene mutated in nonsyndromic hearing impairment. Biochimica et biophysica acta 39 12853124
2022 Nitidine chloride induces caspase 3/GSDME-dependent pyroptosis by inhibting PI3K/Akt pathway in lung cancer. Chinese medicine 38 36175965
2021 Mini-Review: GSDME-Mediated Pyroptosis in Diabetic Nephropathy. Frontiers in pharmacology 37 34867412
2022 Lobaplatin Induces Pyroptosis in Cervical Cancer Cells via the Caspase-3/GSDME Pathway. Anti-cancer agents in medicinal chemistry 36 34666646
2024 Transcription factor Sp1 transcriptionally enhances GSDME expression for pyroptosis. Cell death & disease 34 38238307
2023 Inhibition of CDC20 potentiates anti-tumor immunity through facilitating GSDME-mediated pyroptosis in prostate cancer. Experimental hematology & oncology 34 37528490
2023 Promoting GSDME expression through DNA demethylation to increase chemosensitivity of breast cancer MCF-7 / Taxol cells. PloS one 33 36867605
2020 Methamphetamine induces GSDME-dependent cell death in hippocampal neuronal cells through the endoplasmic reticulum stress pathway. Brain research bulletin 32 32544512
2023 Inhibition of PINK1-Mediated Mitophagy Contributes to Postoperative Cognitive Dysfunction through Activation of Caspase-3/GSDME-Dependent Pyroptosis. ACS chemical neuroscience 31 36946264
2022 Iridium(III) complexes entrapped in liposomes trigger mitochondria-mediated apoptosis and GSDME-mediated pyroptosis. Journal of inorganic biochemistry 31 35033830
2025 Pharmacological activation of STAT1-GSDME pyroptotic circuitry reinforces epigenetic immunotherapy for hepatocellular carcinoma. Gut 30 39486886
2014 A novel splice site mutation in DFNA5 causes late-onset progressive non-syndromic hearing loss in a Chinese family. International journal of pediatric otorhinolaryngology 30 24933359
2023 SNAP25 ameliorates postoperative cognitive dysfunction by facilitating PINK1-dependent mitophagy and impeding caspase-3/GSDME-dependent pyroptosis. Experimental neurology 28 37295545
2014 A DFNA5 mutation identified in Japanese families with autosomal dominant hereditary hearing loss. Annals of human genetics 28 24506266
2022 DFNA5 regulates immune cells infiltration and exhaustion. Cancer cell international 26 35248047
2021 Cordyceps militaris extract induces apoptosis and pyroptosis via caspase-3/PARP/GSDME pathways in A549 cell line. Food science & nutrition 26 35035907
2015 IVS8+1 DelG, a Novel Splice Site Mutation Causing DFNA5 Deafness in a Chinese Family. Chinese medical journal 26 26365971
2007 A novel DFNA5 mutation does not cause hearing loss in an Iranian family. Journal of human genetics 26 17427029
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 25 39215364
2024 Targeting GSDME-mediated macrophage polarization for enhanced antitumor immunity in hepatocellular carcinoma. Cellular & molecular immunology 25 39496854
2022 Blocking Caspase-1/Gsdmd and Caspase-3/-8/Gsdme pyroptotic pathways rescues silicosis in mice. PLoS genetics 24 36459518
2021 Oncostatin M sensitizes keratinocytes to UVB-induced inflammation via GSDME-mediated pyroptosis. Journal of dermatological science 24 34674925
2022 Germacrone induces caspase-3/GSDME activation and enhances ROS production, causing HepG2 pyroptosis. Experimental and therapeutic medicine 23 35747157
2024 GSDME promotes MASLD by regulating pyroptosis, Drp1 citrullination-dependent mitochondrial dynamic, and energy balance in intestine and liver. Cell death and differentiation 22 39009654
2022 Campylobacter jejuni Cytolethal Distending Toxin Induces GSDME-Dependent Pyroptosis in Colonic Epithelial Cells. Frontiers in cellular and infection microbiology 22 35573789
2002 Is DFNA5 a susceptibility gene for age-related hearing impairment? European journal of human genetics : EJHG 22 12461698
2018 Further evidence for "gain-of-function" mechanism of DFNA5 related hearing loss. Scientific reports 21 29849037
2001 Quantification of TECTA and DFNA5 expression in the developing mouse cochlea. Neuroreport 21 11711860
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 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 19 38244230
2024 Gambogic acid induces GSDME dependent pyroptotic signaling pathway via ROS/P53/Mitochondria/Caspase-3 in ovarian cancer cells. Biochemical pharmacology 19 39643123
2021 Plasma membrane perforation by GSDME during apoptosis-driven secondary necrosis. Cellular and molecular life sciences : CMLS 19 34971436
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
2023 Caspase-3/GSDME mediated pyroptosis: A potential pathway for sepsis. International immunopharmacology 18 37837715
2024 ALKBH4 impedes 5-FU Sensitivity through suppressing GSDME induced pyroptosis in gastric cancer. Cell death & disease 17 38902235
2023 Proteasomal inhibitors induce myeloma cell pyroptosis via the BAX/GSDME pathway. Acta pharmacologica Sinica 17 36807412
2023 Endogenous HMGB1 regulates GSDME-mediated pyroptosis via ROS/ERK1/2/caspase-3/GSDME signaling in neuroblastoma. American journal of cancer research 17 36895972
2025 Hypericin photoactivation induces triple-negative breast cancer cells pyroptosis by targeting the ROS/CALR/Caspase-3/GSDME pathway. Journal of advanced research 16 39870303
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 16 39915005
2021 Epithelial-Mesenchymal Transition Induces GSDME Transcriptional Activation for Inflammatory Pyroptosis. Frontiers in cell and developmental biology 16 34901025
2024 Inhibiting apoptosis and GSDME-mediated pyroptosis attenuates hepatic injury in septic mice. Archives of biochemistry and biophysics 15 38408533
2024 Pharmacological inhibition of cGAS ameliorates postoperative cognitive dysfunction by suppressing caspase-3/GSDME-dependent pyroptosis. Neurochemistry international 15 38843953
2023 Exploring the molecular mechanisms of the involvement of GZMB-Caspase-3-GSDME pathway in the progression of rheumatoid arthritis. Molecular immunology 15 37531918
2022 PD-L1 Regulates Platelet Activation and Thrombosis via Caspase-3/GSDME Pathway. Frontiers in pharmacology 15 35784685
2023 Characterization of GSDME in amphioxus provides insights into the functional evolution of GSDM-mediated pyroptosis. PLoS biology 13 37134086
2022 AudioGene: refining the natural history of KCNQ4, GSDME, WFS1, and COCH-associated hearing loss. Human genetics 13 35038006
2024 GSDME-mediated pyroptosis contributes to chemotherapy-induced platelet hyperactivity and thrombotic potential. Blood 12 39378585
2024 Cathepsin L Promotes Pulmonary Hypertension via BMPR2/GSDME-Mediated Pyroptosis. Hypertension (Dallas, Tex. : 1979) 12 39403807
2023 ELP2-NLRP3-GSDMD/GSDME-mediated pyroptosis is induced by TNF-α in MC3T3-E1 cells during osteogenic differentiation. Journal of cellular and molecular medicine 12 37830762
2020 DFNA5 (GSDME) c.991-15_991-13delTTC: Founder Mutation or Mutational Hotspot? International journal of molecular sciences 12 32486382