Gasdermins (GSDMs) are a family of pore-forming proteins that play a central role in pyroptosis, an inflammatory form of programmed cell death.
Upon activation, gasdermins create pores in the plasma membrane, leading to cell swelling, membrane rupture, and release of inflammatory cytokines (IL-1β, IL-18). These mediators of pyroptosis (as opposed to apoptosis), are closely associated with systemic cytotoxicity or so-called side effects and are also involved in the inflammatory response during chemotherapy.
1. Gasdermin Family Members
The gasdermin family includes six members in humans and five in mice:
| Gasdermin | Expression & Function |
|---|---|
| GSDMA | Found in skin, esophagus, stomach, role in epithelial homeostasis & cancer. |
| GSDMB | Expressed in epithelial tissues, involved in asthma & autoimmune diseases. |
| GSDMC | Linked to cancer cell pyroptosis and drug resistance. |
| GSDMD | Key pyroptosis executor, activated by caspase-1, -4, -5, -11. |
| GSDME (DFNA5) | Involved in apoptotic-to-pyroptotic switch, cancer suppression. |
| PJVK (DFNB59) | Important for inner ear function & hearing (not pore-forming). |
2. Mechanism of Gasdermin Activation
Gasdermins exist in an inactive, autoinhibited form. Activation requires proteolytic cleavage by caspases or granzymes, separating the N-terminal pore-forming domain from the C-terminal autoinhibitory domain.
Key Activation Pathways:
-
Pyroptosis Pathway (GSDMD)
- Caspase-1 (canonical) or Caspase-4, -5, -11 (non-canonical) cleave GSDMD.
- GSDMD N-terminal domain inserts into the plasma membrane, forming pores (~10-15 nm diameter).
- Pores allow ion influx, osmotic swelling, cell rupture, and IL-1β/IL-18 release.
-
Apoptotic-to-Pyroptotic Switch (GSDME)
- Caspase-3 cleaves GSDME, converting apoptosis into pyroptosis.
- This occurs in cancer cells and enhances anti-tumor immune responses.
-
Cancer-Associated Pyroptosis (GSDMC)
- Activated by caspase-8 under hypoxia in cancer cells.
- Promotes inflammation, metastasis, and drug resistance.
3. Functions of Gasdermins
A. Inflammation & Host Defense
- Pyroptosis eliminates infected or damaged cells, preventing pathogen spread.
- Gasdermin pores allow cytokine release (IL-1β, IL-18) to amplify immune responses.
B. Cancer & Tumor Immunity
- GSDME-mediated pyroptosis enhances immune system attack on tumors.
- GSDMC promotes cancer progression under stress conditions.
C. Autoimmune & Inflammatory Diseases
- Excessive gasdermin activation leads to sepsis, atherosclerosis, neurodegeneration, and inflammatory bowel disease (IBD).
D. Hearing Loss (GSDME/PJVK Mutations)
- GSDME mutations are linked to hereditary deafness.
- PJVK (DFNB59) is crucial for auditory neuron function.
4. Gasdermins in Disease
| Disease | Gasdermin Involvement |
|---|---|
| Infections (Sepsis, COVID-19, TB, HIV) | GSDMD-driven pyroptosis worsens inflammation. |
| Neurodegenerative Diseases (Alzheimer’s, Parkinson’s, ALS) | Inflammasome activation and pyroptosis contribute to neuronal damage. |
| Cancer | GSDME promotes anti-tumor immunity, while GSDMC promotes cancer cell survival. |
| Atherosclerosis & Cardiovascular Disease | Macrophage pyroptosis (GSDMD) promotes plaque rupture. |
| Inflammatory Diseases (IBD, Rheumatoid Arthritis, Asthma) | Excessive pyroptosis exacerbates tissue damage. |
Therapeutic Targeting of Gasdermins
🔹 Inflammasome Inhibitors – Prevent GSDMD activation (e.g., MCC950 for NLRP3 inhibition).
🔹 Caspase Inhibitors – Block GSDMD and GSDME cleavage, reducing pyroptosis.
🔹 Gasdermin Pore Blockers – Target GSDMD to prevent membrane rupture.
🔹 GSDME Activation in Cancer – Inducing pyroptosis in tumors enhances immunotherapy response.
Gasdermins (GSDMs) are central players in pyroptosis, inflammation, cancer, and immune regulation, making them potential therapeutic targets. Current strategies aim to either inhibit gasdermin-driven inflammation (for autoimmune diseases, sepsis, and neurodegeneration) or induce gasdermin-mediated pyroptosis (for cancer immunotherapy).
1. Inhibiting Gasdermin-Mediated Pyroptosis (Anti-Inflammatory Approach)
Overactivation of GSDMD or GSDME contributes to sepsis, inflammatory diseases, neurodegeneration, and cardiovascular disorders. Therapeutic strategies focus on:
A. Inflammasome Inhibitors (Preventing GSDMD Activation)
- MCC950 (CP-456,773) → NLRP3 inhibitor, blocks caspase-1 activation, preventing GSDMD cleavage.
- Used for sepsis, atherosclerosis, inflammatory bowel disease (IBD), and neuroinflammation.
- Oltipraz → Blocks NLRP3 inflammasome assembly, reducing pyroptosis.
- Dapansutrile (OLT1177) → NLRP3-specific inhibitor in clinical trials for gout and cardiovascular inflammation.
B. Caspase Inhibitors (Blocking Gasdermin Cleavage)
- VX-765 (Belnacasan) → Caspase-1 inhibitor, prevents GSDMD cleavage.
- Tested in rheumatoid arthritis, epilepsy, and neuroinflammation.
- Z-YVAD-FMK → Inhibits caspase-1, reducing IL-1β release and pyroptosis.
- Z-LEVD-FMK → Caspase-4/-5 inhibitor, blocking non-canonical pyroptosis.
- Emricasan (IDN-6556) → Broad caspase inhibitor, tested in liver diseases and inflammation.
C. Gasdermin Inhibitors (Blocking Pore Formation)
- Disulfiram → FDA-approved alcoholism drug, repurposed to block GSDMD pores.
- Protects against sepsis, IBD, and cytokine storms (COVID-19 studies).
- Necrosulfonamide (NSA) → Selectively inhibits GSDMD pore formation.
- Bay 11-7082 → Suppresses inflammasome activation and gasdermin-driven pyroptosis.
2. Inducing Gasdermin-Mediated Pyroptosis (Anti-Cancer Approach)
In cancer therapy, activating pyroptosis in tumor cells enhances immune responses and immunotherapy effectiveness. Strategies include:
A. Chemotherapy-Induced Pyroptosis (GSDME Activation)
Some chemotherapy drugs (e.g., doxorubicin, cisplatin) activate caspase-3, which cleaves GSDME, switching apoptosis to pyroptosis and increasing tumor immunogenicity.
- Drugs targeting GSDME activation in tumors:
- Doxorubicin
- Cisplatin
- Paclitaxel
B. Granzyme B–Mediated Pyroptosis (Boosting Immunotherapy)
- Granzyme B (GZMB), released by cytotoxic T cells and NK cells, cleaves GSDME, inducing tumor cell pyroptosis.
- Checkpoint inhibitors (PD-1/PD-L1 blockade) enhance Granzyme B release, boosting gasdermin-driven pyroptosis in cancer therapy.
C. Bacterial Toxin-Based Strategies
- Lipopolysaccharides (LPS) from bacteria activate caspase-4/-5/-11, triggering pyroptosis in tumors.
- Bacterial therapy (e.g., attenuated Salmonella, Listeria) is under investigation for inducing pyroptosis in cancers.
3. Emerging Experimental Approaches
- Small-Molecule Modulators – Novel inhibitors or activators targeting gasdermin family proteins are being developed.
- CRISPR-Based Therapy – Editing gasdermin genes to either suppress or enhance pyroptotic pathways.
- Nanoparticle-Based Drug Delivery – Targeted delivery of gasdermin modulators to specific tissues (e.g., inflamed joints, tumors).
Future Perspectives
✅ For inflammatory diseases: Targeting GSDMD and inflammasomes could revolutionize treatments for sepsis, IBD, cardiovascular disease, and neurodegeneration.
✅ For cancer therapy: Activating GSDME-mediated pyroptosis enhances immunotherapy effectiveness, offering a novel strategy for resistant tumors.
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