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gsdmd

Properties1
aliasesgasdermin D, GSDMDC1, DFNA5L, FKSG10

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GSDMD (Gasdermin D)

The executioner of pyroptosis: a 484-amino-acid (~53 kDa) cytosolic protein that is activated by inflammatory caspase cleavage to generate a pore-forming N-terminal fragment. Pore formation lyses the cell (pyroptosis) and releases IL-1β and IL-18 into the extracellular space. As GSDMD-mediated pyroptosis is a driver of sterile inflammation, it is increasingly recognized as a mechanism underlying inflammaging across multiple tissues.

Identity

  • UniProt: P57764 (GSDMD_HUMAN)
  • NCBI Gene: 79792
  • HGNC: 25697
  • Ensembl: ENSG00000104518
  • Mouse ortholog: Gsdmd (one-to-one ortholog)
  • Length: 484 amino acids (canonical isoform)
  • Molecular mass: ~53 kDa (full-length precursor); ~30 kDa (GSDMD-N after cleavage); ~22 kDa (GSDMD-C)
  • Family: Gasdermin superfamily — six human paralogs: GSDMA, GSDMB, GSDMC, GSDMD, GSDME (DFNA5), PJVK (DFNB59)

Domain architecture

GSDMD has a bipartite structure held in autoinhibited conformation in the full-length precursor 1:

FragmentResiduesRole
N-terminal domain (GSDMD-N)1–275Pore-forming; contains transmembrane β-strands (91–97, 103–108, 180–186, 191–197)
Linker helix-loop277–296Contains caspase cleavage site; mediates intramolecular autoinhibition
C-terminal domain (GSDMD-C)276–484Autoinhibitory; blocks GSDMD-N membrane-binding surface in the resting state

The C-terminal domain occludes the lipid-binding and oligomerization surfaces of GSDMD-N; caspase cleavage at Asp-275 separates them, releasing GSDMD-N to engage the membrane 1.

Function: pore formation and pyroptosis

Upon caspase cleavage at Asp-275, liberated GSDMD-N:

  1. Preferentially binds phosphoinositides (PI(4,5)P2, PI(3,4,5)P3) and cardiolipin on the inner leaflet of the plasma membrane (and mitochondrial inner membrane for cardiolipin).
  2. Oligomerizes to form a ring — cryo-EM shows ~27 monomers assemble into a pore with an ~18 nm inner diameter 2; earlier cryo-EM models proposed ~16-mer species but the 27-mer / 18 nm figure is now the consensus cited by subsequent structural work.
  3. Pore-driven osmotic influx triggers cell swelling and membrane rupture (pyroptosis), releasing cytosolic contents including mature IL-1β and IL-18 3.

Pyroptosis is morphologically distinct from apoptosis (no blebbing, rapid lysis, pro-inflammatory) and from necroptosis (GSDMD-independent, MLKL-pore driven). GSDMD is the shared terminal effector for both canonical and non-canonical inflammasome pathways.

An inactivating cleavage also exists: caspase-3/7 can cleave at Asp-87 within GSDMD-N, generating a ~13 kDa fragment and abrogating pore activity — a potential anti-inflammatory counter-regulatory mechanism no-mechanism (physiological significance under-characterized).

Canonical vs non-canonical activation

Canonical (caspase-1)

PAMPs/DAMPs → pattern-recognition receptor (e.g., nlrp3) → NLRP3 inflammasome → ASC oligomerization → caspase-1 autoactivation → cleavage of both GSDMD (at Asp-275) and pro-IL-1β/pro-IL-18 (maturation). Both events are caspase-1 substrates and occur simultaneously 3.

Non-canonical (caspase-11 in mouse; caspase-4/5 in human)

Cytosolic LPS (from intracellular Gram-negative bacteria or outer membrane vesicles) directly binds and activates caspase-11 (mouse) or caspase-4/caspase-5 (human) without requiring an inflammasome scaffold — these caspases then cleave GSDMD directly 4. Non-canonical activation can secondarily trigger NLRP3 activation via potassium efflux through the GSDMD pore, linking the two pathways.

Additional activating caspases

UniProt also records caspase-8 as a cleavage enzyme at Asp-275 (relevant in LPS-primed macrophages and certain apoptotic contexts). Caspase-3/7 cleavage at Asp-87 is inactivating (above).

CaspaseCleavage siteEffectPathway context
Caspase-1Asp-275ActivatingCanonical inflammasome
Caspase-4/5 (human)Asp-275ActivatingNon-canonical LPS sensing
Caspase-11 (mouse)Asp-275ActivatingNon-canonical LPS sensing
Caspase-8Asp-275ActivatingTLR/apoptotic context
Caspase-3/7Asp-87InactivatingApoptosis (counter-regulatory)

Aging relevance and inflammaging

Pyroptosis contributes to inflammaging — the sterile, low-grade chronic inflammation characteristic of older organisms — through several tissue-specific mechanisms:

  • Macrophage/monocyte pyroptosis — elevated NLRP3 inflammasome priming with age drives increased caspase-1 activity and GSDMD cleavage; Mejias et al. 2018 detected elevated cleaved gasdermin-D fragments and increased ASC oligomerization (pyroptosome formation) in brain tissue (cortex and hippocampus) of aged BALB/c mice (18 months) vs. young (3 months); the same study found elevated ASC and IL-18 (not GSDMD) in human serum of males >45 y/o vs. 20–45 y/o (n=17–40 per group) 5. needs-human-replication (direct GSDMD pyroptosis quantification in human tissue not demonstrated)
  • Cardiomyocyte and vascular pyroptosis — GSDMD-mediated pyroptosis implicated in atherosclerotic plaque instability and cardiac remodeling; GSDMD-deficient mice show reduced vascular inflammation in disease models needs-human-replication.
  • Neuroinflammation — microglial pyroptosis via NLRP3/GSDMD axis proposed as a contributor to neurodegenerative age-related disease; mechanistic work predominantly in rodent models needs-human-replication.

The NLRP3/GSDMD/IL-1β axis is the mechanistic thread connecting nlrp3-inflammasome activity to the chronic-inflammation hallmark of aging.

DimensionStatusNotes
Pathway conserved in humans?yesCaspase-4/5 in humans are functional orthologs of mouse caspase-11; GSDMD cleavage site conserved
Phenotype conserved in humans?partialNLRP3/IL-1β/ASC activation documented in aged human blood (ASC, IL-18 elevated in males >45 y/o 5); GSDMD-specific pyroptosis in human tissue requires more direct measurement
Replicated in humans?partialElevated ASC and IL-18 in aged human serum 5; GSDMD protein elevation documented in aged mouse brain (not human serum); no human GSDMD-knockout or therapeutic reduction data

Pharmacology

Disulfiram (DSF) — covalent GSDMD inhibitor

Disulfiram (tetraethylthiuram disulfide; an FDA-approved alcohol-aversion drug) and its metabolite diethyldithiocarbamate (DTC) covalently modify Cys-191 of human GSDMD-N (the analogous residue in mouse Gsdmd is Cys-192), blocking membrane insertion without affecting caspase cleavage of GSDMD 6. Key findings:

  • DSF inhibited canonical (NLRP3/nigericin) pyroptosis in human THP-1 macrophages with cellular IC50 of 7.7 ± 0.3 µM, and non-canonical (LPS electroporation) pyroptosis in mouse iBMDMs with IC50 of 10.3 ± 0.5 µM; IL-1β/IL-18 secretion was blocked at equivalent concentrations 6.
  • Systemic DSF (50 mg/kg IP, C57BL/6J mice) protected against LPS-induced lethal sepsis: at 15 mg/kg LPS, 8/8 DSF-treated mice survived vs. 3/8 controls (p=0.045 at 96 h) 6. needs-human-replication
  • Cys-191 (human) / Cys-192 (mouse) is conserved in GSDMD but absent in other gasdermin family members (GSDMA, GSDMB, GSDMC, GSDME/DFNA5) — the structural basis for DSF’s selectivity for GSDMD pore formation over other gasdermins 6. needs-replication (selectivity characterized in Hu 2020; independent structural replication desirable)

DSF is an existing generic drug with a known safety profile, making GSDMD a translatable aging-inflammation target if a pyroptosis-driven indication is established in humans. Clinical-stage GSDMD-specific inhibitors remain in early development as of 2026.

Necrosulfonamide (NSA)

NSA was initially described as an MLKL inhibitor (necroptosis pathway) and was reported to inhibit GSDMD-mediated pyroptosis. However, Hu 2020 demonstrated that NSA’s activity in the GSDMD liposome leakage assay is attributable primarily to caspase inhibition (NSA inhibits caspase-1 processing of GSDMD) rather than direct modification of GSDMD pore-forming residues — in contrast to DSF, which acts post-cleavage on GSDMD-NT 6. The earlier claim that NSA reacts with Cys-192 of human GSDMD-N is inconsistent with Hu 2020: Cys-192 is the mouse residue; the human residue is Cys-191. NSA is not a selective GSDMD pore inhibitor and is not a clinical candidate. needs-replication

Pathway membership

  • nlrp3-inflammasome — receives caspase-1 output; GSDMD is the terminal effector
  • pyroptosis — GSDMD pore is the defining molecular event
  • chronic-inflammation — GSDMD-dependent IL-1β/IL-18 release is a primary sterile-inflammation driver

Key interactors

  • caspase-1 — canonical activating cleavage at Asp-275
  • caspase-4 / caspase-5 — non-canonical activating cleavage (human)
  • asc — inflammasome adaptor; upstream of caspase-1
  • nlrp3 — canonical sensor, upstream
  • il-1beta — co-released through GSDMD pore / upon pyroptotic rupture
  • il-18 — co-released; downstream effector of inflammasome activation

Cross-references to R24d sibling pages

Limitations and gaps

  • needs-human-replication — Direct evidence that GSDMD-mediated pyroptosis contributes to human inflammaging requires longitudinal or interventional human data; current evidence is from mouse brain studies (Mejias 2018) and cross-sectional human serum studies of upstream markers (ASC, IL-18) rather than GSDMD itself in human tissue.
  • needs-replication — Disulfiram’s Cys-191-specific GSDMD inhibition mechanism was characterized in a single in-vivo study (Hu 2020); independent replication of the selectivity and in-vivo efficacy is needed.
  • no-mechanism — Physiological significance of the inactivating caspase-3/7 cleavage at Asp-87 is not established; whether this represents meaningful counter-regulation during apoptosis or is incidental is unknown.
  • long-term-unknown — Whether chronic low-level GSDMD activation (sub-pyroptotic, as reported for cytokine secretion without full lysis) is quantitatively important for inflammaging chronology is untested.
  • needs-canonical-id — GenAge entry: not listed in GenAge HAGR as of 2026-05-06 (GSDMD not a direct longevity gene; upstream regulators NLRP3 and caspase-1 are the proximal target entries).

Footnotes

Footnotes

  1. doi:10.1038/nature18590 · Ding J et al. · Nature 2016 · in-vitro (crystal structure) · model: full-length GSDMD structure; defined autoinhibition mechanism and pore-forming surface; cited >2600 times ↩ ↩2

  2. doi:10.1038/nature18629 · Liu X et al. · Nature 2016 · in-vitro (cryo-EM + liposome) · model: reconstituted GSDMD pore; paper is not_oa (no local PDF); per consensus of citing literature (Hu 2020 + Pan 2018 cryo-EM), ~27-mer assembly with ~18 nm inner diameter is the accepted pore architecture; cited >3000 times · no-fulltext-access (pore stoichiometry cross-referenced from Hu 2020) ↩

  3. doi:10.1038/nature15514 · Shi J et al. · Nature 2015 · in-vitro + in-vivo · n=multiple cell lines + mouse models · model: macrophage pyroptosis; identified GSDMD as the pyroptotic effector cleaved by caspase-1/11; cited >6100 times ↩ ↩2

  4. doi:10.1038/nature15541 · Kayagaki N et al. · Nature 2015 · in-vivo (mouse) · n=multiple genetic models · model: independent discovery that caspase-11 cleaves GSDMD for non-canonical inflammasome signalling; cited >3400 times ↩

  5. doi:10.1186/s12950-018-0198-3 · Mejias NH et al. · Journal of Inflammation 2018 · in-vivo (mouse) + observational (human serum) · mouse arm: n=5/group (BALB/c, 3 vs. 18 months); human arm: n=17–40/group (males 20–45 y/o vs. >45 y/o) · GSDMD elevation documented in mouse brain tissue (cortex + hippocampus); ASC and IL-18 (not GSDMD) elevated in human serum of older males; increased pyroptosome formation (ASC oligomerization) in aged mouse brain ↩ ↩2 ↩3

  6. doi:10.1038/s41590-020-0669-6 · Hu JJ et al. · Nature Immunology 2020 · in-vitro + in-vivo (mouse) · model: BMDM pyroptosis assay + LPS-sepsis mouse model; disulfiram blocks Cys-191 of GSDMD-N; cited >1000 times ↩ ↩2 ↩3 ↩4 ↩5

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