From pyroptosis, apoptosis and necroptosis to PANoptosis: A mechanistic compendium of programmed cell death pathways
Open accessAbstract
Pyroptosis, apoptosis and necroptosis are the most genetically well-defined programmed cell death (PCD) pathways, and they are intricately involved in both homeostasis and disease. Although the identification of key initiators, effectors and executioners in each of these three PCD pathways has historically delineated them as distinct, growing evidence has highlighted extensive crosstalk among them. These observations have led to the establishment of the concept of PANoptosis, defined as an inflammatory PCD pathway regulated by the PANoptosome complex with key features of pyroptosis, apoptosis and/or necroptosis that cannot be accounted for by any of these PCD pathways alone. In this review, we provide a brief overview of the research history of pyroptosis, apoptosis and necroptosis. We then examine the intricate crosstalk among these PCD pathways to discuss the current evidence for PANoptosis. We also detail the molecular evidence for the assembly of the PANoptosome complex, a molecular scaffold for contemporaneous engagement of key molecules from pyroptosis, apoptosis, and/or necroptosis. PANoptosis is now known to be critically involved in many diseases, including infection, sterile inflammation and cancer, and future discovery of novel PANoptotic components will continue to broaden our understanding of the fundamental processes of cell death and inform the development of new therapeutics.
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PANoptosis is a united modality of inflammatory programmed cell death, accompanied by markers of apoptosis, necrosis, and pyroptosis pathways.
“PANoptosis, is a united modality of inflammatory programmed cell death, accompanied by markers of apoptosis, necrosis, and pyroptosis pathways.271–275”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [275]
The Introduction (page unavailable) describes PANoptosis as a united modality of inflammatory programmed cell death involving markers of three pathways. It names those pathways as pyroptosis, apoptosis, and necroptosis—not necrosis, as the citing sentence says. (LLM, conf=0.85)
Experimental — accuracy not yet measuredCytokines or PAMPs trigger the assembly of a multiprotein complex called the PANoptosome.
“Cytokines or PAMPs trigger the assembly of a multiprotein complex called the PANoptosome.”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [275]
The PANoptosome assembly section (Fig. 3; page unavailable) describes a specific trigger, such as influenza A virus, activating a sensor that initiates assembly of the multiprotein PANoptosome. The inflammatory-diseases section says TNF and IFN-γ induce PANoptosis, but does not establish that cytokines trigger PANoptosome assembly; the paper also does not establish PAMPs as a general class of assembly triggers. (LLM, conf=0.83)
Experimental — accuracy not yet measuredTNF-α and IFN-γ released from PANoptosis play a critical role in driving cytokine storms during infections and inflammatory conditions.
“This highlights the critical role of TNF-α and IFN-γ released from PANoptosis in driving cytokine storms during infections and inflammatory conditions.275”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [275]
In “PANoptosis in inflammatory diseases and cancer” (page unavailable), the paper links PANoptosis-mediated cytokine production to cytokine storms during infection and inflammation. It says TNF and IFN-γ synergistically induce PANoptosis, however, not that those two cytokines are released from PANoptosis; the claimed direction of their release is unsupported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe PANoptosome includes various molecules necessary for the activation of downstream programmed cell death (PCD) effectors such as GSDMD, GSDME, CASP3/7, and MLKL.
“This complex includes various molecules necessary for the activation of downstream programmed cell death (PCD) effectors such as GSDMD, GSDME, CASP3/7, and MLKL (Fig. 4).”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [275]
Influenza A virus was first discovered to cause PANoptosis, followed by many other infections, of bacterial, fungal, and viral origin.
“Influenza A virus was first discovered to cause PANoptosis, followed by many other infections, of bacterial, fungal, and viral origin.275”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [275]
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- [257]Karki Rajendra Kanneganti Thirumala-Devi The ‘cytokine storm’: molecular mechanisms and therapeutic prospects Trends in Immunology 42 8 2021 681 705 34217595 PMC9310545
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Sorted by citations
Inflammation and aging: signaling pathways and intervention therapies
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“This highlights the critical role of TNF-α and IFN-γ released from PANoptosis in driving cytokine storms during infections and inflammatory conditions.(275) Cytokines or PAMPs trigger the assembly of a multiprotein complex called the PANoptosome.”
BackgroundSelf-citationLee, E., Song, C.-H., Bae, S.-J., Ha, K.-T., & Karki, R. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-01069-y · Cited by 164 · see citing works
- Authors
- Wang, Y., & Kanneganti, T.-D.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Kanneganti, Thirumala-Devi
- Venue
- Computational and Structural Biotechnology Journal
- Published
- 2021-01
- Volume
- 19
- Pages
- 4641-4657
- ISSN
- 2001-0370 (ISSN-L)
- PMC
- PMC8405902
- OpenAlex
- W3193190854
- Cited by
- 545
- References
- 259
- Citations by year
- 2026: 94 · 2025: 155 · 2024: 124 · 2023: 101 · 2022: 66 · 2021: 5
- FWCI
- 7.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Computational and Structural Biotechnology Journal (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health
- National Cancer Institute (CA253095)
- National Institute of Allergy and Infectious Diseases (AI101935, AI124346, AI160179)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR056296)
- American Lebanese Syrian Associated Charities
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- PANoptosis, pyroptosis, apoptosis, necroptosis, programmed cell death, inflammatory cell death, sterile inflammation, infection, cancer
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