Affinage

GSDMD

Gasdermin-D · UniProt P57764

Length
484 aa
Mass
52.8 kDa
Annotated
2026-06-10
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GSDMD is the terminal pore-forming executioner of pyroptosis, an inflammatory programmed cell death triggered by inflammatory caspase activation (PMID:26375003). In its resting state GSDMD is autoinhibited: the first loop of the C-terminal gasdermin-C domain inserts into the N-terminal gasdermin-N domain, masking a positively charged oligomerization surface; inflammatory caspases-1, -4, -5, and -11 cleave the interdomain linker to liberate GSDMD-NT, which is both necessary and sufficient to kill the cell (PMID:26375003, PMID:28928145). Caspase recognition occurs through a conserved hydrophobic interface on GSDMD-C engaged by the autoprocessed caspase p10 fragment, allowing cleavage independently of the canonical tetrapeptide site (PMID:32109412). Freed GSDMD-NT inserts into the plasma membrane as monomers and then oligomerizes into large pores, a temporal order resolved by intracellular nanobodies that block oligomerization without preventing membrane insertion (PMID:39327452); this trafficking is gated by a palmitoylation cycle in which DHHC7 palmitoylates C192 and APT2 subsequently depalmitoylates it to license oligomerization (PMID:38538834). The resulting pores drive pyroptotic lysis, IL-1β/IL-18 release, and calcium influx, the last of which recruits the ESCRT-III machinery (CHMP4B, VPS4A) to repair damaged membrane and antagonize pyroptosis (PMID:30467171, PMID:37931722). GSDMD operates across canonical (NLRP3, NLRC4, NLRP1b, Pyrin, AIM2) and noncanonical inflammasome platforms and also lies downstream of caspase-8 in a FADD-restrained epithelial death pathway (PMID:35899491, PMID:32362323). GSDMD-NT additionally localizes to mitochondria, causing aggregation, oxidative stress, and mtDNA leakage that activates STING/cGAS signaling (PMID:40067887, PMID:38695170). Expression is controlled transcriptionally by IRF2 binding a unique promoter element (PMID:31113851), and GSDMD activity is further tuned by acetylation at K248 (reversed by HDAC4), K33-linked ubiquitination at K51 by TRIM21 directing p62-mediated autophagic degradation, and O-GlcNAcylation at S338 that blocks caspase engagement (PMID:38326336, PMID:39824372, PMID:37962578). GSDMD can also be activated pharmacologically without cleavage, and its pore can be blocked by small molecules and covalent cysteine modifiers, establishing it as a therapeutic target in sepsis, ischemia/reperfusion, and tumor immunity (PMID:39243763, PMID:37782407, PMID:39848475).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2015 High

    Established GSDMD as the essential effector of pyroptosis, answering what links inflammatory caspase activation to inflammatory cell death and cytokine release.

    Evidence Genome-wide CRISPR screen in mouse macrophages with GSDMD knockout and domain-mapping constructs

    PMID:26375003

    Open questions at the time
    • Structural basis of autoinhibition not yet defined
    • Mechanism of membrane pore assembly unknown
    • Caspase recognition mode not resolved
  2. 2017 High

    Resolved the structural logic of autoinhibition and oligomerization, explaining how cleavage converts a dormant protein into a membrane-disrupting effector.

    Evidence Crystal structure of GSDMD-C, SAXS of full-length GSDMD, and mutagenesis with cell-death and bactericidal assays

    PMID:28928145

    Open questions at the time
    • Pore architecture in the membrane not visualized
    • Order of membrane insertion vs oligomerization unresolved
  3. 2018 High

    Identified a cell-intrinsic brake on pyroptosis, showing pore-induced calcium influx triggers ESCRT-III membrane repair to limit cell death.

    Evidence Live-cell calcium imaging with genetic and pharmacological ESCRT-III inhibition in human and murine macrophages

    PMID:30467171

    Open questions at the time
    • Direct physical link between GSDMD pores and ESCRT recruitment not defined here
    • Stoichiometry of repair vs pore formation unknown
  4. 2019 High

    Defined transcriptional control of GSDMD, showing IRF2 sets the cellular threshold for inflammasome competence.

    Evidence ENU mutagenesis screen, IRF2 knockout cells/tissues, and promoter binding assays

    PMID:31113851

    Open questions at the time
    • Signals upstream of IRF2 not defined
    • Other transcriptional regulators not excluded
  5. 2020 High

    Explained how caspases recognize GSDMD independently of a tetrapeptide motif, identifying a conserved C-domain hydrophobic interface engaged by autoprocessed caspase p10.

    Evidence Crystal structures of caspase-4/11- and caspase-1-GSDMD-C complexes with biochemical and cellular validation

    PMID:32109412

    Open questions at the time
    • Whether all caspases use identical interface kinetics unclear
    • Regulation of caspase-GSDMD docking in cells not addressed
  6. 2020 High

    Positioned GSDMD downstream of caspase-8 in a FADD-restrained epithelial death pathway distinct from necroptosis, broadening its pathway context beyond inflammatory caspases.

    Evidence Genetic epistasis with IEC-specific FADD, caspase-8, MLKL, and GSDMD knockout combinations in mice

    PMID:32362323

    Open questions at the time
    • Direct caspase-8 cleavage of GSDMD not biochemically shown here
    • Tissue specificity of this pathway unclear
  7. 2022 High

    Delineated GSDMD's role across inflammasome platforms in neutrophils and dissociated it from NETosis, clarifying which neutrophil functions depend on GSDMD.

    Evidence GSDMD-knockout neutrophils with multiple canonical inflammasome activators and PMA-NETosis assays

    PMID:35899491

    Open questions at the time
    • Conditions under which GSDMD contributes to NETs remained unresolved
    • Neutrophil-specific pore dynamics not measured
  8. 2024 High

    Identified a palmitoylation/depalmitoylation cycle (DHHC7, APT2) at C192 that gates GSDMD trafficking and pore assembly, adding a lipid-modification checkpoint to activation.

    Evidence Acyl-RAC assays, C192 mutagenesis, DHHC7/APT2 perturbation, and in vivo LPS sepsis models

    PMID:38538834

    Open questions at the time
    • Spatial coordination of palmitoylation cycle with caspase cleavage unclear
    • Whether the cycle applies to all activation routes unknown
  9. 2024 High

    Resolved the kinetic order of pore formation, showing GSDMD-NT inserts as monomers before oligomerizing, and that blocking oligomerization reroutes death to apoptosis.

    Evidence Intracellular and extracellular nanobodies with membrane partitioning and caspase activity readouts

    PMID:39327452

    Open questions at the time
    • Structure of the inserted monomer intermediate not determined
    • In vivo relevance of pyroptosis-to-apoptosis switch not tested
  10. 2024 High

    Demonstrated GSDMD pores can be activated pharmacologically without cleavage and exploited for antitumor immunity, decoupling pore formation from proteolytic processing.

    Evidence High-throughput chemical screen identifying DMB with liposome leakage and tumor models

    PMID:39243763

    Open questions at the time
    • Mechanism by which DMB bypasses autoinhibition not fully defined
    • Selectivity over other gasdermins not detailed here
  11. 2024 High

    Established GSDMD-NT mitochondrial localization as a direct driver of organelle dysfunction and oxidative stress, expanding pore action beyond the plasma membrane.

    Evidence Gsdmd-KO mice, pharmacological inhibition, and microscopy/ROS assays in cochlear cells

    PMID:40067887

    Open questions at the time
    • Targeting signal directing GSDMD-NT to mitochondria unknown
    • Relative contribution of mitochondrial vs plasma membrane pores unresolved
  12. 2024 Medium

    Mapped post-transcriptional and post-translational control nodes (acetylation/HDAC4, K33-ubiquitination/TRIM21-p62, O-GlcNAcylation, m6A, 2'-O-methylation) that tune GSDMD abundance and activation.

    Evidence Mass spectrometry, site-directed mutagenesis, writer/eraser/reader identification, and RNA-modification assays across multiple disease models

    PMID:37962578 PMID:38326336 PMID:39450788 PMID:39627574 PMID:39824372

    Open questions at the time
    • Cross-talk and hierarchy among modifications not established
    • Most are single-lab findings without independent replication
    • Physiological contexts in which each modification dominates unclear
  13. 2024 Medium

    Connected GSDMD to context-dependent disease outcomes via mtDNA-STING signaling, cytokine-driven tissue damage, and intercellular transfer of GSDMD-N-bearing mitochondria.

    Evidence Tissue-specific KO/knockdown mice in atherosclerosis, sepsis, and ischemia/reperfusion with pathway and microvesicle transfer assays

    PMID:35783187 PMID:36906959 PMID:37794018 PMID:38169726 PMID:38632402 PMID:38695170 PMID:39227368

    Open questions at the time
    • Direct biochemical mechanism of intercellular GSDMD transfer not fully resolved
    • Acute vs chronic dual roles of GSDMD remain context-dependent
    • Many findings are single-lab disease-model studies

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unified structural model of the assembled GSDMD membrane pore, the determinants of mitochondrial versus plasma-membrane targeting, and the integration of competing PTM checkpoints into a single regulatory logic remain unresolved.
  • No high-resolution structure of the assembled pore in the timeline
  • Mechanism selecting mitochondrial vs plasma membrane localization unknown
  • Hierarchy among transcriptional, RNA, and protein modifications unestablished

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0008289 lipid binding 2
Localization
GO:0005886 plasma membrane 3 GO:0005739 mitochondrion 2 GO:0005829 cytosol 2
Pathway
R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
APT2CASP1CASP11CASP4CHMP4BDHHC7TRIM21VPS4A

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 Inflammatory caspases (caspase-1, -4, -5, and -11) cleave GSDMD at the linker between the N-terminal gasdermin-N domain and C-terminal gasdermin-C domain. Cleavage releases the intramolecular autoinhibition imposed by the C-terminal domain on the N-terminal domain, and the freed N-terminal domain is necessary and sufficient to induce pyroptotic cell death. GSDMD-deficient cells resist pyroptosis induced by cytosolic LPS and canonical inflammasome ligands, and IL-1β release is diminished despite intact caspase-1 processing. CRISPR-Cas9 genome-wide screen in mouse bone marrow macrophages; GSDMD knockout cells; domain-mapping experiments with cleavage-resistant and N-terminal-only constructs Nature High 26375003
2017 Crystal structure of the human GSDMD C-terminal domain (2.64 Å) reveals that the first loop of GSDMD-C inserts into GSDMD-N to stabilize autoinhibited conformation. The positive-potential surface of GSDMD-N (covered by GSDMD-C in the intact protein) is exposed after caspase cleavage and drives high-order oligomerization via charge-charge interactions. A short segment of GSDMD-N is sufficient to kill bacteria in vitro. SAXS envelope of human GSDMD is consistent with an autoinhibited conformation in solution. X-ray crystallography (GSDMD-C, 2.64 Å); small-angle X-ray scattering (SAXS); site-directed mutagenesis (F283A/F283R); cell-death assays in 293T cells; in vitro bactericidal assay Proceedings of the National Academy of Sciences of the United States of America High 28928145
2020 Autoprocessing of caspase-4/11 generates a p10 fragment that binds the GSDMD C-terminal domain with high affinity via a hydrophobic interface induced by the autoprocessing-generated β-sheet. Crystal structures of autoprocessed caspase-4/11–GSDMD-C and caspase-1–GSDMD-C complexes reveal a conserved C-domain recognition mode. This C-domain binding promotes dimerization-mediated caspase activation and allows cleavage of GSDMD independently of the canonical cleavage-site tetrapeptide sequence. Crystal structures of caspase-4/11-GSDMD-C and caspase-1-GSDMD-C complexes; biochemical binding assays; autoprocessing mutants; pyroptosis cell assays Cell High 32109412
2018 Calcium influx through GSDMD pores in the plasma membrane serves as a signal for cells to recruit the ESCRT-III membrane-repair machinery to damaged membrane areas. Inhibition of ESCRT-III strongly enhances pyroptosis and IL-1β release after canonical or noncanonical inflammasome activation, demonstrating that ESCRT-mediated membrane repair acts downstream of GSDMD pore formation to counteract pyroptotic cell death. Live-cell calcium imaging; pharmacological and genetic inhibition of ESCRT-III; LDH/IL-1β release assays in human and murine macrophages Science High 30467171
2019 IRF2, an interferon regulatory factor family transcription factor, binds a unique site in the GSDMD promoter and is required for GSDMD transcription. IRF2-deficient macrophages, endothelial cells, and multiple tissues show substantially reduced GSDMD expression, with corresponding reductions in IL-1β secretion and pyroptosis. Disruption of the single IRF2-binding site abolishes both canonical and noncanonical inflammasome signaling. Forward genetic ENU mutagenesis screen in mice; IRF2 knockout macrophages and tissues; promoter binding assays; IL-1β secretion and pyroptosis assays Science signaling High 31113851
2024 GSDMD undergoes reversible S-palmitoylation at C192 during pyroptosis. The palmitoyl acyltransferase DHHC7 palmitoylates full-length GSDMD to direct its cleavage by caspases. Palmitoylation of the released GSDMD N-terminal fragment (GSDMD-NT) promotes its translocation to the plasma membrane, where the depalmitoylase APT2 then removes the palmitoyl group to unmask C192 and promote GSDMD-NT oligomerization and pore formation. Perturbation of either palmitoylation or depalmitoylation suppresses pyroptosis and increases survival in LPS-induced septic shock. Acyl-RAC palmitoylation assays; site-directed mutagenesis of C192; DHHC7 and APT2 knockout/knockdown; subcellular fractionation; in vivo LPS sepsis model with GSDMD-KO and enzyme-KO mice Nature cell biology High 38538834
2024 In brain endothelial cells (bECs), LPS is internalized via the LBP-CD14 pathway and activates caspase-11 (CASP11), which cleaves GSDMD to cause plasma membrane permeabilization and pyroptosis, leading to BBB disruption. Mice deficient in LBP-CD14 or GSDMD resist LPS-induced BBB breakdown. bEC-targeted delivery of active GSDMD-N opens the BBB independently of LPS. A GSDMD-neutralizing nanobody expressed in bECs prevents K. pneumoniae infection-induced BBB disruption in CASP4-humanized mice. Mouse genetics (GSDMD-KO, LBP/CD14-KO, CASP4-humanized mice); bEC-targeting AAV nanobody delivery; electron microscopy of disrupted BBB; in vitro pyroptosis assays; single-cell RNA-seq Nature High 38632402
2024 Nanobodies (VHHs) raised against human GSDMD that are expressed cytosolically prevent GSDMD-NT oligomerization but not membrane insertion, showing that membrane insertion of GSDMD-NT monomers precedes oligomerization during pore formation. Inhibition of GSDMD pore formation by nanobodies switches cell death from pyroptosis to apoptosis, driven by enhanced caspase-1 activity activating caspase-3. Recombinant antagonistic nanobodies added extracellularly also prevent pyroptosis. Intracellular nanobody expression; extracellular nanobody addition; GSDMD-NT membrane partitioning assays; caspase activity assays; live-cell death readouts Nature communications High 39327452
2020 GSDMD-mediated pore formation in endothelial cells in response to cytosolic LPS does not cause cell death but instead restrains endothelial cell proliferation (mitochondrial GSDMD pores DAMPen pyroptosis context discussed in this commentary describing the Huang et al. finding). Commentary/perspective summarizing primary experimental findings from Huang et al. regarding endothelial GSDMD pores and cell proliferation Immunity Low 32187511
2023 GI-Y1, identified by structure-based virtual screening, binds GSDMD and inhibits its lipid-binding and pore formation by targeting the Arg7 residue of GSDMD-N. GI-Y1 also inhibits mitochondrial binding of GSDMD-N and associated mitochondrial dysfunction, and protects against myocardial I/R injury in vivo. Structure-based virtual screening; direct binding assays; site-directed mutagenesis of Arg7; liposome binding assay; in vivo myocardial I/R mouse model Basic research in cardiology Medium 37782407
2024 GSDMD is acetylated at Lysine 248, and this acetylation enhances pyroptosis. HDAC4 acts as the specific deacetylase that deacetylates GSDMD at K248, suppressing pyroptosis. Deacetylation of GSDMD impairs its ubiquitination. Phosphorylation of HDAC4 promotes its deacetylase activity toward GSDMD. Protein phosphatase 1 (PP1α and PP1γ) dephosphorylates HDAC4 to inhibit its deacetylase activity on GSDMD, thereby enabling acetylation and pyroptosis. Mass spectrometry identification of acetylation site; site-directed mutagenesis of K248; HDAC4 knockdown/overexpression; PP1 knockdown; ubiquitination assays; in vitro and in vivo pyroptosis assays Cell death & disease Medium 38326336
2023 O-GlcNAcylation of GSDMD at Serine 338 (S338) prevents its interaction with caspase-11 (caspase-4 homolog) and thereby inhibits LPS-induced pyroptosis in endothelial cells. Increased O-GlcNAc stimulation in septic mice reduces endothelial injury and GSDMD cleavage. O-GlcNAcylation site prediction and gene mutation (S338A); Co-IP to assess caspase-4/GSDMD interaction; OGA inhibitor thiamet-G treatment in HUVECs and septic mice; western blot for GSDMD cleavage Inflammation research Medium 37962578
2025 The E3 ligase TRIM21 catalyzes K33-linked polyubiquitination of GSDMD-NT at Lys51, enabling recognition by the cargo receptor SQSTM1/p62 and subsequent selective autophagy-mediated degradation of p30/GSDMD-NT. Scutellarin exploits this pathway to inhibit pyroptosis by degrading p30/GSDMD-NT and by blocking ASC oligomerization. Ubiquitination assays with linkage-specific antibodies; K51R mutagenesis; TRIM21 and p62 knockdown; autophagy flux assays; multiple inflammasome activation models Pharmacological research Medium 39824372
2024 METTL3-mediated m6A modification of GSDMD mRNA is recognized by the m6A reader YTHDF2, which decreases GSDMD mRNA stability and suppresses GSDMD-mediated pyroptosis in breast cancer cells. METTL3 inhibition restores GSDMD expression and enhances pyroptosis. m6A-seq/MeRIP; YTHDF2 RIP assay; mRNA stability assays; METTL3 and YTHDF2 knockdown/overexpression; pyroptosis readouts; in vivo tumor model with METTL3 inhibitor Apoptosis Medium 39627574
2024 SNORD99 promotes 2'-O-methylation of GSDMD mRNA, forming a SNORD99-FBL RNP complex. This modification reduces GSDMD protein levels, thereby suppressing caspase-1/NLRP3-dependent pyroptosis and promoting endometrial cancer progression. RTL-P assay for 2'-O-methylation; RNA-seq after SNORD99 overexpression; co-immunoprecipitation of SNORD99-FBL RNP; ASO-mediated SNORD99 suppression; western blot for GSDMD/caspase-1/NLRP3; electron/optical microscopy of pyroptosis Journal of cellular and molecular medicine Medium 39450788
2024 GSDMD contributes to mitochondrial dysfunction during pyroptosis: the pore-forming N-terminal of GSDMD localizes to mitochondria (in addition to the plasma membrane) following caspase-dependent cleavage, causing abnormal mitochondrial aggregation and oxidative stress in cochlear marginal cells, which drives inflammation, stria vascularis damage, and cisplatin-induced hearing loss. Gsdmd-KO mice; pharmacological GSDMD inhibition (necrosulfonamide, disulfiram); confocal and electron microscopy for GSDMD-N mitochondrial localization; ROS/membrane potential assays; RNA-seq; cochlear histology Proceedings of the National Academy of Sciences of the United States of America High 40067887
2024 A small molecule DMB (6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline) directly activates GSDMD pore formation and pyroptosis without requiring caspase-mediated cleavage of GSDMD, demonstrating that GSDMD can be activated independently of proteolytic processing. Low-level DMB-induced pyroptosis in tumor cells stimulates immune-mediated antitumor responses. High-throughput chemical screen; direct GSDMD pore-formation assays; liposome leakage; tumor models in lymphocyte-deficient mice; cytokine measurements; anti-PD-1 combination studies Cell High 39243763
2022 Canonical inflammasomes (NLRP3, NLRC4, NLRP1b, Pyrin, AIM2) all promote GSDMD cleavage in neutrophils, and canonical inflammasome-induced pyroptosis and IL-1β secretion are blunted in GSDMD-knockout neutrophils. In contrast, GSDMD is dispensable for PMA-induced NETosis in neutrophils. GSDMD-KO bone marrow neutrophils; multiple canonical inflammasome activators; NLRP3 gain-of-function (Nlrp3-A350V) transgenic mice; LDH/IL-1β/pyroptosis readouts; PMA-NETosis assay EMBO reports High 35899491
2025 In an experimental sepsis model, NET formation was independent of GSDMD (and PAD4) but required MYD88, indicating that GSDMD is not required for sepsis-induced intravascular NET formation in vivo. Pharmacological GSDMD inhibitors did not reduce PMA-stimulated NET formation ex vivo. Gsdmd/D1/D1l3-/- triple knockout mice; LPS/E. coli sepsis model; pharmacological GSDMD inhibitors; ex vivo PMA-NET assay FASEB journal Medium 39777764
2020 Caspase-8 and GSDMD are both required for the development of MLKL-independent ileitis in mice with epithelial FADD deficiency, placing GSDMD downstream of caspase-8 in a pyroptosis-like death pathway in intestinal epithelial cells that is distinct from necroptosis. Genetic epistasis: IEC-specific FADD-KO, caspase-8-KO, MLKL-KO, GSDMD-KO mice and combinations; histological assessment of colitis/ileitis Immunity High 32362323
2022 GSDMD deficiency in cardiomyocytes (cardiomyocyte-specific CKO) reduces TAC-induced pyroptosis, myocardial hypertrophy, and fibrosis. GSDMD-mediated pyroptosis in this context activates JNK and p38 signaling pathways (but not ERK or Akt), linking GSDMD-driven pyroptosis to downstream kinase-mediated cardiac remodeling. Cardiomyocyte-specific GSDMD-CKO mice; TAC-induced pressure overload; echocardiography; western blot for JNK/p38/ERK/Akt phosphorylation; histology Clinical and experimental hypertension Medium 36906959
2024 GSDMD in macrophages contributes to mitochondrial perforation and mitochondrial DNA leakage, subsequently activating the STING-IRF3/NF-κB axis. GSDMD also regulates macrophage migration via cytokine secretion in the context of atherosclerosis. Gsdmd-/-ApoE-/- mice; bone marrow transplantation; AAV-F4/80-shGSDMD macrophage-specific knockdown; single-cell RNA-seq; STING pathway analysis; mtDNA leakage assays Arteriosclerosis, thrombosis, and vascular biology Medium 38695170
2023 GSDMD-NT from pyroptotic macrophage-derived microvesicles (containing GSDMD-N-expressing mitochondria) is transferred to neutrophils via microvesicles, inducing mitochondrial dysfunction and triggering NETs formation through the mitochondrial ROS/GSDMD axis in the context of sepsis. Macrophage-neutrophil co-culture with microvesicles; flow cytometry; confocal microscopy for mitochondrial transfer; mtROS measurement; disulfiram (GSDMD inhibitor) in vivo sepsis model International journal of biological sciences Medium 38169726
2022 GSDMD knockout in GSDMD-/- mice or GSDMD knockdown (dimethyl fumarate) inhibits GSDMD activation and reduces NETs formation and mitochondrial DNA leakage into the neutrophil cytosol. GSDMD causes mtDNA to leak into the cytosol during lung ischemia/reperfusion, activating the cGAS-STING pathway and stimulating NETs formation. GSDMD-KO mice; disulfiram pharmacological inhibition; mtDNA cytoplasmic fractionation; cGAS-STING pathway inhibition; in vivo lung I/R model Cell death discovery Medium 37794018
2023 CHMP4B and VPS4A (ESCRT-III components) interact with GSDMD (confirmed by Co-IP) and localize as puncta at injured plasma membranes containing GSDMD-NT. Depletion of CHMP4B or VPS4A enhances GSDMD-mediated pore formation and pyroptotic indicators, while overexpression reduces them, demonstrating that the ESCRT machinery directly counteracts GSDMD pores through membrane remodeling in endometrial carcinoma cells. Co-immunoprecipitation of GSDMD with CHMP4B and VPS4A; siRNA knockdown and overexpression; electron microscopy of membrane perforations; fluorescence confocal microscopy of CHMP4B/VPS4A puncta at GSDMD-NT membrane sites; PI/LDH/IL-1β/Ca2+ assays Biochimica et biophysica acta. General subjects Medium 37931722
2022 GSDMD deficiency in the acute phase of myocardial I/R protects the heart, but in the chronic phase GSDMD deficiency aggravates injury. Mechanistically, GSDMD deficiency induces activation of poly(ADP-ribosyl)ation (PARylation) and consumption of NAD+ and ATP, leading to cardiomyocyte apoptosis. PARP-1 inhibitor PJ34 reduces injury caused by GSDMD deficiency. GSDMD-KO mice; acute and chronic I/R timepoints; PARylation assays; NAD+/ATP measurements; PJ34 pharmacological rescue; western blot and histology Oxidative medicine and cellular longevity Medium 35783187
2024 JX06 covalently modifies Cys39/Cys192 residues of GSDMD, inhibiting accumulation of GSDMD-NT and pore formation in the plasma membrane, thereby suppressing PANoptosis and multiple organ injury in heat stress and sepsis models. Covalent modification mass spectrometry; GSDMD-KO rescue experiments; in vitro pore-formation assays; in vivo heat stress and sepsis MODS models; cell death assays Biochemical pharmacology Medium 39848475
2024 GSDMD knockout reduces skeletal muscle atrophy in septic mice by blocking the IL-18/AMPK signaling pathway, and specifically reduces markers of the ubiquitin-proteasome system and autophagy pathways. GSDMD-NT levels are elevated in skeletal muscle of septic mice, linking pyroptosis execution by GSDMD to downstream IL-18 secretion that drives muscle wasting via AMPK. Gsdmd-KO mice; CLP sepsis model; siRNA knockdown in C2C12 cells; AMPK phosphorylation assays; muscle atrophy marker expression (Atrogin-1, MuRF1); IL-18 measurements Shock Medium 39227368

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 5373 26375003
2020 Structural Mechanism for GSDMD Targeting by Autoprocessed Caspases in Pyroptosis. Cell 599 32109412
2018 ESCRT-dependent membrane repair negatively regulates pyroptosis downstream of GSDMD activation. Science (New York, N.Y.) 597 30467171
2021 NLRP3/caspase-1/GSDMD-mediated pyroptosis exerts a crucial role in astrocyte pathological injury in mouse model of depression. JCI insight 290 34877938
2021 GSDMD-Mediated Cardiomyocyte Pyroptosis Promotes Myocardial I/R Injury. Circulation research 288 34015941
2020 Metformin protects against intestinal ischemia-reperfusion injury and cell pyroptosis via TXNIP-NLRP3-GSDMD pathway. Redox biology 287 32330868
2021 Cisplatin Induces Pyroptosis via Activation of MEG3/NLRP3/caspase-1/GSDMD Pathway in Triple-Negative Breast Cancer. International journal of biological sciences 251 34326697
2022 Polystyrene microplastics-induced cardiotoxicity in chickens via the ROS-driven NF-κB-NLRP3-GSDMD and AMPK-PGC-1α axes. The Science of the total environment 238 35714743
2020 FADD and Caspase-8 Regulate Gut Homeostasis and Inflammation by Controlling MLKL- and GSDMD-Mediated Death of Intestinal Epithelial Cells. Immunity 234 32362323
2017 Structure insight of GSDMD reveals the basis of GSDMD autoinhibition in cell pyroptosis. Proceedings of the National Academy of Sciences of the United States of America 232 28928145
2024 Brain endothelial GSDMD activation mediates inflammatory BBB breakdown. Nature 214 38632402
2019 IRF2 transcriptionally induces GSDMD expression for pyroptosis. Science signaling 154 31113851
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
2024 A palmitoylation-depalmitoylation relay spatiotemporally controls GSDMD activation in pyroptosis. Nature cell biology 115 38538834
2022 GSDMD-dependent neutrophil extracellular traps promote macrophage-to-myofibroblast transition and renal fibrosis in obstructive nephropathy. Cell death & disease 114 35941120
2021 Acinar cell NLRP3 inflammasome and gasdermin D (GSDMD) activation mediates pyroptosis and systemic inflammation in acute pancreatitis. British journal of pharmacology 107 33871879
2022 Astragaloside IV attenuate MI-induced myocardial fibrosis and cardiac remodeling by inhibiting ROS/caspase-1/GSDMD signaling pathway. Cell cycle (Georgetown, Tex.) 100 35770948
2021 Inflammasome-mediated GSDMD activation facilitates escape of Candida albicans from macrophages. Nature communications 85 34795266
2021 GSDMD-mediated pyroptosis: a critical mechanism of diabetic nephropathy. Expert reviews in molecular medicine 84 34955116
2022 Didymin Suppresses Microglia Pyroptosis and Neuroinflammation Through the Asc/Caspase-1/GSDMD Pathway Following Experimental Intracerebral Hemorrhage. Frontiers in immunology 82 35154128
2021 Trimetazidine attenuates dexamethasone-induced muscle atrophy via inhibiting NLRP3/GSDMD pathway-mediated pyroptosis. Cell death discovery 82 34537816
2022 The Regulation and Modification of GSDMD Signaling in Diseases. Frontiers in immunology 81 35774778
2024 Small-molecule GSDMD agonism in tumors stimulates antitumor immunity without toxicity. Cell 77 39243763
2022 GSDMD drives canonical inflammasome-induced neutrophil pyroptosis and is dispensable for NETosis. EMBO reports 75 35899491
2023 Ursolic Acid Alleviates Neuroinflammation after Intracerebral Hemorrhage by Mediating Microglial Pyroptosis via the NF-κB/NLRP3/GSDMD Pathway. International journal of molecular sciences 68 37834220
2021 Pyroptosis executive protein GSDMD as a biomarker for diagnosis and identification of Alzheimer's disease. Brain and behavior 68 33587329
2024 Pyroptotic Macrophage-Derived Microvesicles Accelerate Formation of Neutrophil Extracellular Traps via GSDMD-N-expressing Mitochondrial Transfer during Sepsis. International journal of biological sciences 66 38169726
2022 Myoglobin promotes macrophage polarization to M1 type and pyroptosis via the RIG-I/Caspase1/GSDMD signaling pathway in CS-AKI. Cell death discovery 66 35228524
2023 Efficient Delivery of GSDMD-N mRNA by Engineered Extracellular Vesicles Induces Pyroptosis for Enhanced Immunotherapy. Small (Weinheim an der Bergstrasse, Germany) 63 36635060
2022 Targeting of GSDMD sensitizes HCC to anti-PD-1 by activating cGAS pathway and downregulating PD-L1 expression. Journal for immunotherapy of cancer 63 35688553
2024 Macrophage-Derived GSDMD Plays an Essential Role in Atherosclerosis and Cross Talk Between Macrophages via the Mitochondria-STING-IRF3/NF-κB Axis. Arteriosclerosis, thrombosis, and vascular biology 60 38695170
2023 ERRα promotes glycolytic metabolism and targets the NLRP3/caspase-1/GSDMD pathway to regulate pyroptosis in endometrial cancer. Journal of experimental & clinical cancer research : CR 57 37864196
2023 Simvastatin induces pyroptosis via ROS/caspase-1/GSDMD pathway in colon cancer. Cell communication and signaling : CCS 54 37974278
2023 GSDMD promotes neutrophil extracellular traps via mtDNA-cGAS-STING pathway during lung ischemia/reperfusion. Cell death discovery 52 37794018
2024 Inhibition of HDAC2 sensitises antitumour therapy by promoting NLRP3/GSDMD-mediated pyroptosis in colorectal cancer. Clinical and translational medicine 51 38804602
2019 Gasdermin D (GSDMD) as a new target for the treatment of infection. MedChemComm 47 31191857
2021 Hirudin ameliorates diabetic nephropathy by inhibiting Gsdmd-mediated pyroptosis. Cell biology and toxicology 46 34212273
2024 Pyroptosis-mediator GSDMD promotes Parkinson's disease pathology via microglial activation and dopaminergic neuronal death. Brain, behavior, and immunity 45 38552923
2023 Puerarin Inhibits NLRP3-Caspase-1-GSDMD-Mediated Pyroptosis via P2X7 Receptor in Cardiomyocytes and Macrophages. International journal of molecular sciences 44 37685976
2023 Novel GSDMD inhibitor GI-Y1 protects heart against pyroptosis and ischemia/reperfusion injury by blocking pyroptotic pore formation. Basic research in cardiology 41 37782407
2020 Mitochondrial GSDMD Pores DAMPen Pyroptosis. Immunity 38 32187511
2022 Review: the role of GSDMD in sepsis. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 35 35969260
2022 Involvement of NLRP3/Caspase-1/GSDMD-Dependent pyroptosis in BPA-Induced apoptosis of human neuroblastoma cells. Biochemical pharmacology 34 35439536
2023 Hepatic TNFRSF12A promotes bile acid-induced hepatocyte pyroptosis through NFκB/Caspase-1/GSDMD signaling in cholestasis. Cell death discovery 33 36690641
2025 GSDMD-mediated pyroptosis: molecular mechanisms, diseases and therapeutic targets. Molecular biomedicine 32 39994107
2024 Targeting the smooth muscle cell Keap1-Nrf2-GSDMD-pyroptosis axis by cryptotanshinone prevents abdominal aortic aneurysm formation. Theranostics 31 39479449
2023 PD-L1 promotes GSDMD-mediated NET release by maintaining the transcriptional activity of Stat3 in sepsis-associated encephalopathy. International journal of biological sciences 30 37056920
2023 LDC7559 inhibits microglial activation and GSDMD-dependent pyroptosis after subarachnoid hemorrhage. Frontiers in immunology 30 37063846
2022 GSDMD contributes to myocardial reperfusion injury by regulating pyroptosis. Frontiers in immunology 30 36217543
2022 Ablation of GSDMD Attenuates Neurological Deficits and Neuropathological Alterations After Traumatic Brain Injury. Frontiers in cellular neuroscience 28 35669106
2022 Oridonin Protects against Myocardial Ischemia-Reperfusion Injury by Inhibiting GSDMD-Mediated Pyroptosis. Genes 27 36421808
2024 Targeting STING elicits GSDMD-dependent pyroptosis and boosts anti-tumor immunity in renal cell carcinoma. Oncogene 26 38548966
2024 Antagonistic nanobodies implicate mechanism of GSDMD pore formation and potential therapeutic application. Nature communications 26 39327452
2023 Anti-inflammatory effect of Danhong injection through inhibition of GSDMD-mediated pyroptosis. Phytomedicine : international journal of phytotherapy and phytopharmacology 26 36893672
2022 Blocking Caspase-1/Gsdmd and Caspase-3/-8/Gsdme pyroptotic pathways rescues silicosis in mice. PLoS genetics 25 36459518
2024 Caspase-11/GSDMD contributes to the progression of hyperuricemic nephropathy by promoting NETs formation. Cellular and molecular life sciences : CMLS 24 38436813
2024 Lipocalin-2-mediated intestinal epithelial cells pyroptosis via NF-κB/NLRP3/GSDMD signaling axis adversely affects inflammation in colitis. Biochimica et biophysica acta. Molecular basis of disease 23 38844113
2024 P2X7R Modulates NEK7-NLRP3 Interaction to Exacerbate Experimental Autoimmune Prostatitis via GSDMD-mediated Prostate Epithelial Cell Pyroptosis. International journal of biological sciences 21 38993566
2022 GSDMD-mediated pyroptosis in retinal vascular inflammatory diseases: a review. International ophthalmology 21 36068399
2023 GSDMD deficiency ameliorates hyperoxia-induced BPD and ROP in neonatal mice. Scientific reports 20 36599874
2023 Enteric fungi protect against intestinal ischemia-reperfusion injury via inhibiting the SAA1-GSDMD pathway. Journal of advanced research 19 37717911
2022 mTORC1-Dependent and GSDMD-Mediated Pyroptosis in Developmental Sevoflurane Neurotoxicity. Molecular neurobiology 19 36224321
2024 Macrophage-derived GSDMD promotes abdominal aortic aneurysm and aortic smooth muscle cells pyroptosis. International immunopharmacology 17 38262162
2024 EZH2-STAT3 signaling pathway regulates GSDMD-mediated pyroptosis in glioblastoma. Cell death discovery 17 39069522
2023 O-GlcNAc modification of GSDMD attenuates LPS-induced endothelial cells pyroptosis. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 17 37962578
2022 Ceramide induces pyroptosis through TXNIP/NLRP3/GSDMD pathway in HUVECs. BMC molecular and cell biology 17 36517743
2024 Crosstalk of HDAC4, PP1, and GSDMD in controlling pyroptosis. Cell death & disease 16 38326336
2024 Paeoniflorin inhibited GSDMD to alleviate ANIT-induced cholestasis via pyroptosis signaling pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 16 39255724
2025 HERV-W Env Induces Neuron Pyroptosis via the NLRP3-CASP1-GSDMD Pathway in Recent-Onset Schizophrenia. International journal of molecular sciences 14 39859234
2024 Igniting hope: Harnessing NLRP3 inflammasome-GSDMD-mediated pyroptosis for cancer immunotherapy. Life sciences 14 39127315
2023 CHMP4B and VSP4A reverse GSDMD-mediated pyroptosis by cell membrane remodeling in endometrial carcinoma. Biochimica et biophysica acta. General subjects 13 37931722
2022 Inhibition of GSDMD Activates Poly(ADP-ribosyl)ation and Promotes Myocardial Ischemia-Reperfusion Injury. Oxidative medicine and cellular longevity 13 35783187
2025 Cordycepin attenuates NLRP3/Caspase-1/GSDMD-mediated LPS-induced macrophage pyroptosis. Frontiers in pharmacology 12 40028157
2023 GSDMD gene knockout alleviates hyperoxia-induced hippocampal brain injury in neonatal mice. Journal of neuroinflammation 12 37679766
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
2025 Inhibition of Caspase-1 Suppresses GSDMD-mediated Peritoneal Mesothelial Cell Pyroptosis and Inflammation in Peritoneal Fibrosis. Small (Weinheim an der Bergstrasse, Germany) 11 40018871
2024 GSDMD-Dependent Neutrophil Extracellular Traps Mediate Portal Vein Thrombosis and Associated Fibrosis in Cirrhosis. International journal of molecular sciences 11 39201786
2023 GSDMD-mediated pyroptosis promotes cardiac remodeling in pressure overload. Clinical and experimental hypertension (New York, N.Y. : 1993) 11 36906959
2022 Obeticholic acid improved triptolide/lipopolysaccharide-induced hepatotoxicity by inhibiting caspase-11-GSDMD pyroptosis pathway. Journal of applied toxicology : JAT 11 36328986
2022 PKR deficiency delays vascular aging via inhibiting GSDMD-mediated endothelial cell hyperactivation. iScience 11 36691613
2025 Ligilactobacillus Murinus and Lactobacillus Johnsonii Suppress Macrophage Pyroptosis in Atherosclerosis through Butyrate-GPR109A-GSDMD Axis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 10 40726432
2024 Gut microbiota-mediated activation of GSDMD ignites colorectal tumorigenesis. Cancer gene therapy 10 38898209
2024 GSDMD KNOCKOUT ALLEVIATES SEPSIS-ASSOCIATED SKELETAL MUSCLE ATROPHY BY INHIBITING IL18/AMPK SIGNALING. Shock (Augusta, Ga.) 10 39227368
2025 Sepsis-induced NET formation requires MYD88 but is independent of GSDMD and PAD4. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 9 39777764
2024 Hydroxysafflor Yellow A Inhibits Pyroptosis and Protecting HUVECs from OGD/R via NLRP3/Caspase-1/GSDMD Pathway. Chinese journal of integrative medicine 9 38319525
2024 Targeting BRD4 mitigates hepatocellular lipotoxicity by suppressing the NLRP3 inflammasome activation and GSDMD-mediated hepatocyte pyroptosis. Cellular and molecular life sciences : CMLS 9 38977508
2024 SNORD99 promotes endometrial cancer development by inhibiting GSDMD-mediated pyroptosis through 2'-O-methylation modification. Journal of cellular and molecular medicine 9 39450788
2024 Rhaponticin Alleviates Collagen-induced Arthritis by Inhibiting NLRP3/GSDMD-mediated Neutrophil Extracellular Traps. Inflammation 9 39725843
2023 Palmitic acid induces GSDMD-mediated pyroptosis in periodontal ligament cells via the NF-κB pathway. Oral diseases 9 37357358
2023 PIK3CG Regulates NLRP3/GSDMD-Mediated Pyroptosis in Septic Myocardial Injury. Inflammation 9 37676465
2022 Pulsed electromagnetic field alleviates synovitis and inhibits the NLRP3/Caspase-1/GSDMD signaling pathway in osteoarthritis rats. Electromagnetic biology and medicine 9 34994274
2025 Scutellarin inhibits pyroptosis via selective autophagy degradation of p30/GSDMD and suppression of ASC oligomerization. Pharmacological research 8 39824372
2025 TRAF6 promotes abdominal aortic aneurysm development by activating macrophage pyroptosis via the NLRP3/Caspase1/GSDMD pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 8 39831511
2025 Targeting GSDMD JX06 inhibits PANoptosis and multiple organ injury. Biochemical pharmacology 8 39848475
2025 GSDMD-mediated mitochondrial dysfunction in marginal cells: A potential driver of inflammation and stria vascularis damage in CIHL. Proceedings of the National Academy of Sciences of the United States of America 8 40067887
2024 GSDMD induces hepatocyte pyroptosis to trigger alcoholic hepatitis through modulating mitochondrial dysfunction. Cell division 8 38532477
2024 RACK1 and NEK7 mediate GSDMD-dependent macrophage pyroptosis upon Streptococcus suis infection. Veterinary research 8 39334337
2024 The N6-methyladenosine writer METTL3 promotes breast cancer progression through YTHDF2-dependent posttranscriptional silencing of GSDMD. Apoptosis : an international journal on programmed cell death 8 39627574
2024 Astragaloside IV attenuates podocyte apoptosis via regulating TXNIP/NLRP3/GSDMD signaling pathway in diabetic nephropathy. Diabetology & metabolic syndrome 8 39696607
2022 Macrophages promote growth, migration and epithelial-mesenchymal transition of renal cell carcinoma by regulating GSDMD/IL-1β axis. Cytokine 8 36057231

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