Int J Stomatol

Int J Stomatol ›› 2026, Vol. 53 ›› Issue (3): 433-440.doi: 10.7518/gjkq.2026104

• Reviews • Previous Articles    

Research progress of PANoptosis in oral diseases

Xuande Zhu(),Guanhui Chen()   

  1. Dept. of Stomatology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, China
  • Received:2025-01-23 Revised:2025-08-08 Online:2026-05-01 Published:2026-04-24
  • Contact: Guanhui Chen E-mail:zhuxd25@mail2.sysu.edu.cn;chengh86@mail.sysu.edu.cn
  • Supported by:
    National Natural Science Foundation of China(82303794)

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Abstract:

Programmed cell death (PCD) serves as a crucial mechanism for maintaining host innate immunity, homeostasis, and the balance between pathogens and the host. PANoptosis is a novel form of programmed cell death that is primarily regulated by the PANoptosome complex and concurrently exhibits the features of apoptosis, pyroptosis, and necroptosis. Oral diseases, which significantly impact the quality of life and general health of patients, are a major concern. Interest in the underlying mechanisms of PANoptosis involved in oral diseases is currently increasing. This review explains the definition, characteristics, regulatory mechanisms of PANoptosis and its potential relationship with oral di-seases, aiming to offer possible solutions for the detection, prevention, and treatment of oral diseases.

Key words: programmed cell death, PANoptosis, PANoptosome, oral disease

CLC Number: 

  • R780.2

TrendMD: 

Fig 1

Molecular regulation mechanism of PANoptosis"

[1] Newton K, Strasser A, Kayagaki N, et al. Cell death[J]. Cell, 2024, 187(2): 235-256.
[2] Subbarao Malireddi RK, Kesavardhana S, Kanneganti TD. ZBP1 and TAK1: master regulators of NLRP3 inflammasome/pyroptosis, apoptosis, and necroptosis (PAN-optosis) [J]. Front Cell Infect Microbiol, 2019, 9: 406.
[3] Galluzzi L, Vitale I, Aaronson SA, et al. Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018[J]. Cell Death Differ, 2018, 25(3): 486-541.
[4] Moujalled D, Strasser A, Liddell JR. Molecular mechanisms of cell death in neurological diseases[J]. Cell Death Differ, 2021, 28(7): 2029-2044.
[5] Liu X, Xia SY, Zhang ZB, et al. Channelling inflammation: gasdermins in physiology and disease[J]. Nat Rev Drug Discov, 2021, 20(5): 384-405.
[6] Man SM, Karki R, Kanneganti TD. Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious di-seases[J]. Immunol Rev, 2017, 277(1): 61-75.
[7] Laurien L, Nagata M, Schünke H, et al. Autophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation[J]. Nat Commun, 2020, 11(1): 1747.
[8] Samson AL, Zhang Y, Geoghegan ND, et al. MLKL trafficking and accumulation at the plasma membrane control the kinetics and threshold for necroptosis[J]. Nat Commun, 2020, 11: 3151.
[9] Christgen S, Tweedell RE, Kanneganti TD. Programming inflammatory cell death for therapy[J]. Pharmacol Ther, 2022, 232: 108010.
[10] Zheng M, Kanneganti TD. The regulation of the ZBP1-NLRP3 inflammasome and its implications in pyroptosis, apoptosis, and necroptosis (PANoptosis)[J]. Immunol Rev, 2020, 297(1): 26-38.
[11] Lopes JP, Lionakis MS. Pathogenesis and virulence of Candida albicans [J]. Virulence, 2022, 13(1): 89-121.
[12] Place DE, Lee S, Kanneganti TD. PANoptosis in microbial infection[J]. Curr Opin Microbiol, 2021, 59: 42-49.
[13] Chen XT, Dai YF, Li YS, et al. Identification of cross-talk pathways and PANoptosis-related genes in periodontitis and Alzheimer’s disease by bioinformatics analysis and machine learning[J]. Front Aging Neurosci, 2024, 16: 1430290.
[14] Christgen S, Zheng M, Kesavardhana S, et al. Identification of the PANoptosome: a molecular platform triggering pyroptosis, apoptosis, and necroptosis (PANoptosis) [J]. Front Cell Infect Microbiol, 2020, 10: 237.
[15] Jiang S, Li H, Zhang L, et al. Generic diagramming platform (GDP): a comprehensive database of high-quality biomedical graphics[J]. Nucleic Acids Res, 2025, 53(d1): D1670-D1676.
[16] Kuriakose T, Kanneganti TD. ZBP1: innate sensor regulating cell death and inflammation[J]. Trends Immunol, 2018, 39(2): 123-134.
[17] Kesavardhana S, Subbarao Malireddi RK, Burton AR, et al. The Zα2 domain of ZBP1 is a molecular switch regulating influenza-induced PANoptosis and perinatal lethality during development[J]. J Biol Chem, 2020, 295(24): 8325-8330.
[18] Banoth B, Tuladhar S, Karki R, et al. ZBP1 promotes fungi-induced inflammasome activation and pyroptosis, apoptosis, and necroptosis (PANoptosis)[J]. J Biol Chem, 2020, 295(52): 18276-18283.
[19] Zheng M, Karki R, Vogel P, et al. Caspase-6 is a key regulator of innate immunity, inflammasome activation, and host defense[J]. Cell, 2020, 181(3): 674-687.e13.
[20] Karki R, Lee S, Mall R, et al. ZBP1-dependent inflammatory cell death, PANoptosis, and cytokine storm disrupt IFN therapeutic efficacy during coronavirus infection[J]. Sci Immunol, 2022, 7(74): eabo6294.
[21] Lee S, Karki R, Wang YQ, et al. AIM2 forms a complex with pyrin and ZBP1 to drive PANoptosis and host defence[J]. Nature, 2021, 597(7876): 415-419.
[22] Cuny GD, Degterev A. RIPK protein kinase family: atypical lives of typical kinases[J]. Semin Cell Dev Biol, 2021, 109: 96-105.
[23] Subbarao Malireddi RK, Kesavardhana S, Karki R, et al. RIPK1 distinctly regulates Yersinia-induced inflammatory cell death, PANoptosis[J]. Immunohorizons, 2020, 4(12): 789-796.
[24] Dillon CP, Weinlich R, Rodriguez DA, et al. RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3[J]. Cell, 2014, 157(5): 1189-1202.
[25] Dannappel M, Vlantis K, Kumari S, et al. RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis[J]. Nature, 2014, 513(7516): 90-94.
[26] Jin L, Chen J, Liu XY, et al. The double life of RIPK1[J]. Mol Cell Oncol, 2016, 3(1): e1035690.
[27] Geng JF, Ito Y, Shi LY, et al. Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis[J]. Nat Commun, 2017, 8(1): 359.
[28] Subbarao Malireddi RK, Gurung P, Kesavardhana S, et al. Innate immune priming in the absence of TAK1 drives RIPK1 kinase activity-independent pyroptosis, apoptosis, necroptosis, and inflammatory disease[J]. J Exp Med, 2020, 217(3): jem.20191644.
[29] Sundaram B, Pandian N, Mall R, et al. NLRP12-PANoptosome activates PANoptosis and pathology in response to heme and PAMPs[J]. Cell, 2023, 186(13): 2783-2801.e20.
[30] Henkel FDR, O’Neill LAJ. NLRP12 drives PANoptosis in response to heme[J]. Trends Immunol, 2023, 44(8): 574-576.
[31] Zhang AP, Zhang CC, Zhang YH, et al. PANoptosis is a compound death in periodontitis: a systematic review of ex vivo and in vivo studies[J]. Oral Dis, 2024, 30(4): 1828-1842.
[32] Aral K, Aral CA, Kapila Y. The role of caspase-8, caspase-9, and apoptosis inducing factor in perio-dontal disease[J]. J Periodontol, 2019, 90(3): 288-294.
[33] Shi J, Li J, Su W, et al. Loss of periodontal ligament fibroblasts by RIPK3-MLKL-mediated necroptosis in the progress of chronic periodontitis[J]. Sci Rep, 2019, 9(1): 2902.
[34] Bugueno IM, Batool F, Korah L, et al. Porphyromonas gingivalis differentially modulates apoptosome apoptotic peptidase activating factor 1 in epithelial cells and fibroblasts[J]. Am J Pathol, 2018, 188(2): 404-416.
[35] Li YY, Cai Q, Li BS, et al. The effect of Porphyromonas gingivalis lipopolysaccharide on the pyroptosis of gingival fibroblasts[J]. Inflammation, 2021, 44(3): 846-858.
[36] Chen Q, Liu XG, Wang DY, et al. Periodontal inflammation-triggered by periodontal ligament stem cell pyroptosis exacerbates periodontitis[J]. Front Cell Dev Biol, 2021, 9: 663037.
[37] Duan Y, An W, Wu YX, et al. Tetramethylpyrazine reduces inflammation levels and the apoptosis of LPS-stimulated human periodontal ligament cells via the downregulation of miR-302b[J]. Int J Mol Med, 2020, 45(6): 1918-1926.
[38] Oka S, Li XY, Sato F, et al. A deficiency of Dec2 triggers periodontal inflammation and pyroptosis[J]. J Periodontal Res, 2021, 56(3): 492-500.
[39] Sun DD, Wu X, Lin SC, et al. Anti-apoptosis and anti-inflammation activity of circ_0097010 downregulation in lipopolysaccharide-stimulated periodontal ligament cells by miR-769-5p/Krüppel like factor 6 axis[J]. J Dent Sci, 2023, 18(1): 310-321.
[40] Yang YN, Wang LX, Zhang HB, et al. Mixed lineage kinase domain-like pseudokinase-mediated necroptosis aggravates periodontitis progression[J]. J Mol Med (Berl), 2022, 100(1): 77-86.
[41] Ke XJ, Lei L, Li H, et al. Manipulation of necroptosis by Porphyromonas gingivalis in periodontitis development[J]. Mol Immunol, 2016, 77: 8-13.
[42] Li J, Shi JH, Pan Y, et al. Transcription modulation by CDK9 regulates inflammatory genes and RIPK3-MLKL-mediated necroptosis in periodontitis progression[J]. Sci Rep, 2019, 9(1): 17369.
[43] Zhang KY, Chen XX, Zhou R, et al. Inhibition of gingival fibroblast necroptosis mediated by RIPK3/MLKL attenuates periodontitis[J]. J Clin Periodontol, 2023, 50(9): 1264-1279.
[44] Jiang WY, Deng ZL, Dai XZ, et al. PANoptosis: a new insight into oral infectious diseases[J]. Front Immunol, 2021, 12: 789610.
[45] Tomalka J, Ganesan S, Azodi E, et al. A novel role for the NLRC4 inflammasome in mucosal defenses against the fungal pathogen Candida albicans [J]. PLoS Pathog, 2011, 7(12): e1002379.
[46] Cao MT, Wu ZX, Lou Q, et al. Dectin-1-induced RIPK1 and RIPK3 activation protects host against Candida albicans infection[J]. Cell Death Differ, 2019, 26(12): 2622-2636.
[47] Wang X, Li Y, Liu S, et al. Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus 1 (HSV-1) protein ICP6 triggers host antiviral defense[J]. Proc Natl Acad Sci U S A, 2014, 111(43): 15438-15443.
[48] Yu XL, Li Y, Chen Q, et al. Herpes simplex virus 1 (HSV-1) and HSV-2 mediate species-specific modulations of programmed necrosis through the viral ribonucleotide reductase large subunit R1[J]. J Virol, 2015, 90(2): 1088-1095.
[49] Guo HY, Omoto S, Harris PA, et al. Herpes simplex virus suppresses necroptosis in human cells[J]. Cell Host Microbe, 2015, 17(2): 243-251.
[50] Siqueira JF Jr, Rôças IN. Present status and future directions: microbiology of endodontic infections[J]. Int Endod J, 2022, 55(): 512-530.
[51] Liu L, Liang LP, Yang CH, et al. Extracellular vesicles of Fusobacterium nucleatum compromise intestinal barrier through targeting RIPK1-mediated cell death pathway[J]. Gut Microbes, 2021, 13(1): 1-20.
[52] Liu H, Liu YX, Fan W, et al. Fusobacterium nucleatum triggers proinflammatory cell death via Z-DNA binding protein 1 in apical periodontitis[J]. Cell Commun Signal, 2022, 20(1): 196.
[53] Ran S, Chu M, Gu S, et al. Enterococcus faecalis induces apoptosis and pyroptosis of human osteoblastic MG63 cells via the NLRP3 inflammasome[J]. Int Endod J, 2019, 52(1): 44-53.
[54] Dai X, Deng Z, Liang Y, et al. Enterococcus faecalis induces necroptosis in human osteoblastic MG63 cells through the RIPK3/MLKL signalling pathway[J]. Int Endod J, 2020, 53(9): 1204-1215.
[55] Chi DL, Lin XW, Meng QZ, et al. Real-time induction of macrophage apoptosis, pyroptosis, and necro-ptosis by Enterococcus faecalis OG1RF and two root canal isolated strains[J]. Front Cell Infect Microbiol, 2021, 11: 720147.
[56] Mall R, Bynigeri RR, Karki R, et al. Pancancer transcriptomic profiling identifies key PANoptosis mar-kers as therapeutic targets for oncology[J]. NAR Cancer, 2022, 4(4): zcac033.
[57] Karki R, Sundaram B, Sharma BR, et al. ADAR1 restricts ZBP1-mediated immune response and PANoptosis to promote tumorigenesis[J]. Cell Rep, 2021, 37(3): 109858.
[58] Subbarao Malireddi RK, Karki R, Sundaram B, et al. Inflammatory cell death, PANoptosis, mediated by cytokines in diverse cancer lineages inhibits tumor growth[J]. Immunohorizons, 2021, 5(7): 568-580.
[59] Yang P, Huang GZ, Li YL, et al. Identification of PANoptosis-related biomarkers and analysis of prognostic values in head and neck squamous cell carcinoma[J]. Sci Rep, 2024, 14(1): 9824.
[60] Gao F, Zhang MH, Ying ZG, et al. A PANoptosis pattern to predict prognosis and immunotherapy response in head and neck squamous cell carcinoma[J]. Heliyon, 2024, 10(5): e27162.
[61] Jiang XY, Fu TT, Huang L. PANoptosis: a new insight for oral diseases[J]. Mol Biol Rep, 2024, 51(1): 960.
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