Gasdermin D (GSDMD)
Gasdermin D (GSDMD) is a pore-forming effector protein and the principal executioner of pyroptosis, a lytic, inflammatory form of programmed cell death.
Gasdermin D (GSDMD) is a pore-forming effector protein and the principal executioner of pyroptosis, a lytic, inflammatory form of programmed cell death. It belongs to the gasdermin superfamily, which includes closely related paralogs such as Gasdermin E (GSDME). GSDMD is held inactive by an intramolecular clamp: an N-terminal pore-forming domain bound to a C-terminal autoinhibitory domain through a linker. Cleavage within that linker releases the constraint, and the liberated N-terminal fragment (GSDMD-N) binds acidic lipids in the inner leaflet of the plasma membrane, oligomerizes, and inserts to form a large transmembrane pore roughly 20 nm across.
Three routes cut the linker. The canonical one is the inflammatory caspase CASP1 (caspase-1), activated downstream of the NLRP3 inflammasome and other inflammasomes; the noncanonical route runs through caspase-4 and caspase-5 in humans, and caspase-11 in mice, which bind cytosolic lipopolysaccharide directly and so sense Gram-negative invasion without an upstream sensor protein; caspase-8 provides a third route under conditions that block apoptotic signaling. The resulting pores are first a conduit rather than a wound, allowing mature Interleukin-1β (IL-1β) and IL18 to leave a still-intact cell — the same pores can also contribute to neutrophils releasing extracellular traps. Sustained pore formation then draws water inward until the cell swells and ruptures, spilling damage-associated molecular patterns including High Mobility Group Box 1 (high mobility group box 1 (HMGB1)); that terminal rupture is not passive bursting but an execution step carried out by the membrane protein NINJ1.
Upstream, the toll like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor-κB (NF-κB) pathway primes inflammasome components, coupling pattern recognition to eventual GSDMD cleavage. In tumors, cytolytic granzymes delivered by cytotoxic T cell populations and natural killer cell populations trigger the same death program through sibling gasdermins rather than GSDMD itself — granzyme A of the GZMA/GZMB pair cleaving GSDMB and granzyme B cleaving GSDME — which turns immunologically silent apoptosis into inflammatory death and amplifies anti-tumor immunity. This dual character, driving tissue damage in metabolic, fibrotic, autoimmune and ischemia-reperfusion disease while potentially serving anti-tumor immunity, is why GSDMD is pursued from both directions; the covalent inhibitors disulfiram, necrosulfonamide and dimethyl fumarate, each modifying the reactive cysteine required for oligomerization, are the most studied tools for blocking it.
Where the papers sit
10 papers from the last 6 months study Gasdermin D (GSDMD) directly · updated from PubMed 12 Oct 2026
Study type 0 clinical trials · 1 human data · 7 preclinical · 2 unclassified
Themes 3 themes
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Pyroptosis-Driven Cancer Immunity
GSDMD-mediated pyroptosis is being used to turn tumor killing into an immune-priming strategy in colorectal cancer and other malignancies. Salmonella delivery, AMER1-linked dopamine production, nanovesicles, and neoantigen/MICB vaccines converge on antigen release and CD8+ T-cell activation. Caspase-1 and pyroptotic antigen exposure recur as mechanisms for overcoming immune resistance, including PI-resistant myeloma. Whether these platforms can translate beyond engineered or preclinical systems, and which tumor antigens best predict benefit, remains open.
5 papers · 50%
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Caspase-1 Inflammatory Pyroptosis
Inflammatory caspase-1/IL-1β/GSDMD signaling is being explored both as a cancer-killing mechanism and as a therapeutic target in rheumatoid arthritis. ARDAP@SPION-PEI nanocomposites use PANoptosis to eliminate renal cancer cells, whereas Tianyu formulation aims to suppress NLRP3-driven pyroptosis. The shared biology is cytokine maturation and membrane pore formation, but intervention direction differs by disease. Comparative evidence remains limited on whether selective GSDMD blockade or broader inflammasome modulation offers the better balance of efficacy and toxicity.
2 papers · 20%
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Others — Chronic Disease Mechanisms
Pulmonary fibrosis, obesity, and cardiac aging are linked here only loosely through tissue injury, senescence, or NLRP3/GSDMD-associated inflammation. siGSDMD/pDNA-SAP nanoparticles target fibroblast pathology, while the obesity study seeks epigenetic predictors of weight-loss success and the cardiac work implicates TMAO-driven NLRP3 pyroptosis. The papers do not establish a shared therapeutic direction. Their main commonality is interest in molecular markers or interventions for chronic disease, with clinical relevance and cross-disease mechanisms still unresolved.
3 papers · 30%
Papers
The 10 papers from the last 6 months that study Gasdermin D (GSDMD) directly, newest first, by theme and by study type. Study types come from PubMed publication types and MeSH headings.
By theme
Pyroptosis-Driven Cancer Immunity (5)
- Augmenting antitumor immunity in colon cancer via GSDMD-mediated pyroptosis induced by an attenuated Salmonella delivery system. Immunologic research · 4 Oct 2026 PMID 42830389
- Activating a novel cell death pathway to target PI-resistant multiple myeloma and enhance immunogenic cell death. Apoptosis : an international journal on programmed cell death · 7 Sept 2026 PMID 42704369
- Pyroptosis-Amplified Decoy Nanovesicles Orchestrate Pyroptotic Antigen Explosion and Endogenous Immune Revitalization for Potentiating Tumour Immunotherapy. Journal of extracellular vesicles · 28 Aug 2026 PMID 42661498
- Tumoral AMER1 driven dopamine synthesis triggers cancer cell pyroptosis and licenses CD8+ T cell immunity in colorectal cancer. Cancer letters · 3 Aug 2026 PMID 42546913
- Neoantigens and shared MICB α3 antigen dual-targeted vaccine generates potent antitumor immunity. EMBO molecular medicine · 17 Apr 2026 PMID 41998137
Caspase-1 Inflammatory Pyroptosis (2)
- Superparamagnetic iron oxide nanoparticle-driven 3-aroyl-1,4-diarylpyrrole nanocomposites (ARDAP@SPION-PEI) mediate renal cancer cell PANoptosis by regulating chromatin accessibility. Molecular biomedicine · 15 May 2026 PMID 42138776
- The "Tianyu" Formulation Alleviates Rheumatoid Arthritis by Modulating the NLRP3/Caspase-1/GSDMD-Mediated Pyroptosis Pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 25 Apr 2026 PMID 42033182
Others — Chronic Disease Mechanisms (3)
- Trimethylamine N-oxide drives cardiac aging by activating NLRP3-mediated pyroptosis. Life sciences · 9 Jun 2026 PMID 42264141
- Predictive epigenetic biomarkers of successful weight-loss intervention in pre-pubertal children with obesity. Clinical epigenetics · 29 May 2026 PMID 42210364
- Mucus-penetrating lipid nanoparticles overcome lung barriers for pulmonary co-delivery of siGSDMD and pDNA-SAP in idiopathic pulmonary fibrosis. International journal of pharmaceutics · 15 Apr 2026 PMID 41985596
By study type
Human data, design not indexed (1)
- Predictive epigenetic biomarkers of successful weight-loss intervention in pre-pubertal children with obesity. Clinical epigenetics · 29 May 2026 PMID 42210364
Preclinical: animal, cell and lab studies (7)
- Augmenting antitumor immunity in colon cancer via GSDMD-mediated pyroptosis induced by an attenuated Salmonella delivery system. Immunologic research · 4 Oct 2026 PMID 42830389
- Activating a novel cell death pathway to target PI-resistant multiple myeloma and enhance immunogenic cell death. Apoptosis : an international journal on programmed cell death · 7 Sept 2026 PMID 42704369
- Pyroptosis-Amplified Decoy Nanovesicles Orchestrate Pyroptotic Antigen Explosion and Endogenous Immune Revitalization for Potentiating Tumour Immunotherapy. Journal of extracellular vesicles · 28 Aug 2026 PMID 42661498
- Trimethylamine N-oxide drives cardiac aging by activating NLRP3-mediated pyroptosis. Life sciences · 9 Jun 2026 PMID 42264141
- Superparamagnetic iron oxide nanoparticle-driven 3-aroyl-1,4-diarylpyrrole nanocomposites (ARDAP@SPION-PEI) mediate renal cancer cell PANoptosis by regulating chromatin accessibility. Molecular biomedicine · 15 May 2026 PMID 42138776
- The "Tianyu" Formulation Alleviates Rheumatoid Arthritis by Modulating the NLRP3/Caspase-1/GSDMD-Mediated Pyroptosis Pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 25 Apr 2026 PMID 42033182
- Mucus-penetrating lipid nanoparticles overcome lung barriers for pulmonary co-delivery of siGSDMD and pDNA-SAP in idiopathic pulmonary fibrosis. International journal of pharmaceutics · 15 Apr 2026 PMID 41985596
Unclassified: not yet indexed with MeSH (2)
- Tumoral AMER1 driven dopamine synthesis triggers cancer cell pyroptosis and licenses CD8+ T cell immunity in colorectal cancer. Cancer letters · 3 Aug 2026 PMID 42546913
- Neoantigens and shared MICB α3 antigen dual-targeted vaccine generates potent antitumor immunity. EMBO molecular medicine · 17 Apr 2026 PMID 41998137
Written from 10 PubMed abstracts, each one listed by PMID above. Published: 2026-06-15. Last written: 2026-09-09 by GPT. Corrections: 2026-09-26 by GPT. Drafted by language models from published abstracts; not medical advice.