Abstract
Pyroptosis, a novel mode of inflammatory cell death, is executed by membrane pore-forming gasdermin (GSDM) family members in response to extracellular or intracellular injury cues and is characterized by a ballooning cell morphology, plasma membrane rupture and the release of inflammatory mediators such as interleukin-1β (IL-1β), IL-18 and high mobility group protein B1 (HMGB1). It is a key effector mechanism for host immune defence and surveillance against invading pathogens and aberrant cancerous cells, and contributes to the onset and pathogenesis of inflammatory and autoimmune diseases. Manipulating the pore-forming activity of GSDMs and pyroptosis could lead to novel therapeutic strategies. In this Review, we discuss the current knowledge regarding how GSDM-mediated pyroptosis is initiated, executed and regulated, its roles in physiological and pathological processes, and the crosstalk between different modes of programmed cell death. We also highlight the development of drugs that target pyroptotic pathways for disease treatment.
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Acknowledgements
This work was partly supported by the National Natural Science Foundation of China (32425023, 32400723, 32122034), the National Key R&D Program of China (2020YFA0509600), the Shanghai Pilot Program for Basic Research-Chinese Academy of Sciences, Shanghai Branch (JCYJ-SHFY-2021-009), the Strategic Priority Research Program of Chinese Academy of Sciences (XDB0570000), the Innovative Research Team of High-Level Local Universities in Shanghai (SHSMU-ZDCX20211002), the National Postdoctoral Program for Innovative Talents (BX20240395), the Chinese Postdoctoral Science Foundation (2024M753367) and the Shanghai Sailing Program (24YF2754200). X.L. is a SANS Exploration Scholar. The authors apologize to colleagues whose work could not be cited owing to space limitations.
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X.L. and Y.B. researched data for the article, contributed substantially to discussion of the content and wrote the article. X.L. and Y.P. reviewed and/or edited the manuscript before submission.
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Glossary
- Bacterial effector protein
-
A bacteria-encoded toxic protein that is directly injected into host cells through bacterial secretion systems to interfere with host cell functions, especially hijacking antimicrobial immunity to facilitate bacterial proliferation and pathogenesis.
- cGAS–STING pathway
-
An innate immune signalling pathway responsible for recognition of cytosolic aberrant DNA by cyclic GMP–AMP synthase (cGAS) to produce 2′3′-cyclic GMP–AMP (cGAMP) as a second messenger to activate downstream signalling through endoplasmic reticulum (ER)-resident protein stimulator of interferon genes (STING), resulting in the induction of type I interferon and pro-inflammatory cytokines.
- Cold tumours
-
Cold tumours are immunosuppressive tumours that are unresponsive to immune surveillance or immune checkpoint blockade (ICB) therapy.
- Endosomal sorting complexes required for transport
-
(ESCRT). A molecular machinery that drives the invagination of endosomes to form multivesicular bodies that are critical for sorting and transporting membrane proteins.
- Familial Mediterranean fever
-
A genetic inflammatory disease caused by constitutively active mutations in the pyrin-encoding gene (MEFV) and characterized by recurrent fevers as well as pain in the abdomen, chest and joints.
- Goblet cells
-
A group of specialized epithelial cells on the mucosal surface that produce and secrete mucus to maintain mucosal homeostasis.
- Hot tumours
-
Hot tumours can trigger antitumour immune responses and effectively respond to immune checkpoint blockade (ICB) therapy.
- Immune checkpoint blockade
-
(ICB). An antitumour immunotherapy that blocks immunosuppressive checkpoints in cytotoxic T lymphocytes (CTLs) to increase CTL-mediated killing of cancer cells.
- Immune synapses
-
A specialized and highly-ordered cell–cell contact interface between immune cells and their target cells, where cell–cell communications take place.
- Immunologically silent
-
It is characterized by non-immunogenicity as no immune responses are provoked.
- Inflammatory bowel disease
-
A group of chronic inflammatory disorders in the gastrointestinal tract that can be divided into ulcerative colitis with colorectal inflammation and Crohn’s disease characterized by small intestinal inflammation.
- Neonatal-onset multisystem inflammatory disease
-
A rare genetic inflammatory disease caused by gain-of-function mutations in NLRP3 that occurs in infancy and is characterized by an urticaria-like rash, recurrent fever, skeletal dysplasia and pathological changes in the central nervous system including meningitis, intellectual delay and loss of vision or hearing.
- NETosis
-
A form of neutrophil death characterized by the release of neutrophil nuclear DNA and granule proteins forming neutrophil extracellular traps (NETs) to capture and kill the invading pathogens.
- Poly(ADP-ribosyl)ation
-
(PARylation). A type of post-translational protein modification catalysed by poly(ADP-ribose) polymerases that transfer ADP-ribose polymers onto target proteins using NAD+ as a substrate.
- Rheumatoid arthritis
-
A chronic inflammatory autoimmune disease that manifests as pain, swelling and even deformity in joints.
- Triple-negative breast cancer
-
The most aggressive subtype of breast cancer with the worst prognosis, characterized by a lack of three biomarkers, namely, oestrogen receptor, progesterone receptor and epidermal growth factor receptor 2.
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Bai, Y., Pan, Y. & Liu, X. Mechanistic insights into gasdermin-mediated pyroptosis. Nat Rev Mol Cell Biol 26, 501–521 (2025). https://doi.org/10.1038/s41580-025-00837-0
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DOI: https://doi.org/10.1038/s41580-025-00837-0
