Events & News

Events & News

Latest Innovations

Gasdermin-Mediated Pyroptosis: At the Crossroads of Inflammation, Immunity, and Cancer Research

29 July 2025

Latest Innovations

Pyroptosis is a programmed cell death mechanism characterized by cellular swelling, plasma membrane rupture, and the release of pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and interleukin-18 (IL-18). This cell death modality was initially discovered in macrophages combating pathogenic invasion. When cells detect pathogen intrusion, a family of proteins called Gasdermin (GSDM) becomes activated, forming pores in the cell membrane that lead to cellular rupture and death. This process not only eliminates infected cells but also recruits additional immune cells through the release of inflammatory signals, thereby enhancing the immune response.

Pyroptosis differs fundamentally from traditional apoptosis. While apoptosis is an immunologically silent form of cell death that typically does not trigger inflammation, pyroptosis represents a highly inflammatory cell death mechanism capable of rapidly activating the immune system. This distinction confers unique advantages to pyroptosis in the context of pathogen defence and cancer elimination.

Figure 1. Pyroptosis signalling pathway.

The GSDM Family

Gasdermin family proteins serve as the central executioners of pyroptosis. They form pores in the cell membrane, compromising membrane integrity and ultimately causing cell rupture. The pore-forming capacity of GSDM family proteins depends on their ability to bind membrane phospholipids. GSDMD-NT (the N-terminal fragment of GSDMD) can interact with various membrane phospholipids (such as cardiolipin, phosphatidylinositol phosphate, and phosphatidylserine) and form pores in the membrane. These pores not only compromise membrane integrity but also allow the release of small molecular substances (such as IL-1β and IL-18) into the extracellular environment, thereby initiating inflammatory responses[1].

Figure 2. GSDM family overview.

The Dual Role of Pyroptosis

Pyroptosis represents a double-edged sword in cellular homeostasis. Moderate pyroptosis contributes to pathogen and cancer cell clearance. In infection defence, when bacteria or viruses invade, pyroptosis rapidly destroys infected cells while releasing inflammatory signals that recruit immune cells. In cancer cell elimination, cytotoxic T cells can activate GSDMB and GSDME, inducing cancer cell pyroptosis while simultaneously releasing tumor antigens that stimulate broader anti-tumor immune responses.

Conversely, excessive pyroptosis may lead to inflammatory diseases and tissue damage. In sepsis, excessive pyroptosis can cause systemic inflammatory response syndrome and even multiple organ failure. In severe COVID-19 patients, pyroptosis-induced "cytokine storms" may be key to disease progression. Familial Mediterranean fever, neonatal multisystem inflammatory disease, and other conditions are associated with abnormal activation of pyroptotic pathways. Pyroptosis-mediated neuroinflammation and cell death may exacerbate neurodegenerative disorders. The regulation of pyroptosis involves multiple levels, including GSDM protein expression regulation, post-translational modifications, changes in membrane lipid composition, and organelle involvement.

GSDM Protein Expression Regulation and Post-Translational Modifications

GSDM family protein expression is regulated by various epigenetic mechanisms, including DNA methylation and histone deacetylation. GSDMA expression in gastric cancer cells is silenced by DNA methylation and histone deacetylation, while inhibition of DNA methylation and histone deacetylation can restore its expression. GSDM family protein expression is also regulated by alternative splicing, particularly common in cancer cells. Post-translational modifications of GSDM family proteins significantly impact their activity. For instance, GSDMD can be ubiquitinated and degraded by the proteasome, thereby inhibiting its pyroptotic activity. Conversely, GSDMD can be activated through palmitoylation, which promotes its membrane translocation and pore formation.

Figure 3. Regulation of GSDM protein expression and post-translational modifications.

Membrane Lipid Composition and Organelle Involvement in Pyroptosis Regulation

Changes in membrane lipid composition influence pyroptosis. For example, during Mycobacterium tuberculosis infection, the bacterial PtpB protease dephosphorylates phosphatidylinositol phosphate on the host cell membrane, thereby inhibiting GSDMD membrane translocation and pyroptosis

Additionally, endoplasmic reticulum stress and membrane repair mechanisms can regulate pyroptosis by altering membrane lipid composition. Cellular organelles also play crucial roles in pyroptosis. Mitochondrial damage can accelerate pyroptosis, while lysosomal damage can enhance pyroptosis by releasing inflammatory mediators. Pyroptosis is closely associated with the pathogenesis of various diseases, including sepsis, autoimmune diseases, neurodegenerative disorders, and cancer. In sepsis models, excessive GSDMD activation leads to systemic inflammation and tissue damage. In cancer therapy, pyroptosis induction can enhance the efficacy of immune checkpoint inhibitors, thereby improving anti-tumor immune responses.

Figure 4. Regulation of pyroptosis by membrane lipid composition and organelles

Applications of Pyroptosis in Cancer Therapy

Pyroptosis holds immense potential in cancer therapy. However, its role in cancer is highly complex and dichotomous, with its effects on tumor development, progression, metastasis, and the immune microenvironment varying based on multiple factors. On one hand, pyroptosis can activate robust immune responses by releasing pro-inflammatory cytokines (such as IL-1β and IL-18) and cellular contents (such as HMGB1 and ATP), promoting the recruitment and activation of immune cells (including macrophages, dendritic cells, and T cells). This enhances the body's anti-tumor immune capacity and inhibits tumor growth and metastasis. For instance, in certain lung, gastric, breast, hepatocellular, and colorectal cancers, inducing pyroptosis can significantly suppress tumor cell proliferation and migration. On the other hand, excessive or inappropriately regulated pyroptosis may disrupt the immune microenvironment, triggering chronic inflammatory responses that promote tumor invasion and metastasis.

In cancer research, targeting key molecules and pathways of pyroptosis, such as Caspase family proteins, inflammasomes, and Gasdermin proteins, enables precise regulation of pyroptosis to achieve more effective cancer treatment.

Figure 5. Applications of pyroptosis in cancer research[2]

AmBeed: Your Trusted Lab Partner

Fuel up research project with our featured products, including:

A359670: an antibiotic obtained from Streptomyces hygroscopicus, acting as an H+, K+, and Pb2+ ion carrier and as an NLRP3 agonist.

Nigericin sodium salt, CAS: 28643-80-3

A100567: an orally bioactive proagent of VRT-043198, a potent and selective inhibitor of IL-converting enzyme (ICE)/caspase-1 with Kis of 0.8 nM and less than 0.6 nM for caspase-1 and caspase-4, respectively. It inhibits the release of LPS-induced IL-1β and IL-18 by human PBMCs with an IC50 of ~0.7 μM.

VX-765, CAS: 273404-37-8

A448777: a potent, selective, small-molecule inhibitor of NLRP3 with an IC50 of 7.5 nM in BMDMs.

MCC950, CAS: 210826-40-7

A912727: a specific inhibitor of aldehyde-dehydrogenase (ALDH1), used for the treatment of chronic alcoholism by producing an acute sensitivity to alcohol. It also inhibits pyroptosis by blocking gasdermin D pore formation.

Disulfiram, CAS: 97-77-8

Premium quality, high purity, global delivery.

Contact us: sales.lifetech@ambeed.com

References

[1]Bai, Y., Pan, Y. & Liu, X. Mechanistic insights into gasdermin-mediated pyroptosis. Nat Rev Mol Cell Biol 26, 501–521 (2025).

[2]Wei, X., Xie, F., Zhou, X. et al. Role of pyroptosis in inflammation and cancer. Cell Mol Immunol 19, 971–992 (2022).

Prev: Atom Replacement Strategy Achieves Precise Regiocontrol in Pyrazole Alkylation

Next: Skeletal editing of pyrrolidines by nitrogen-atom insertion