Research Progress on PANoptosis and Central Nervous System Diseases

doi:10.3969/j.issn.1673-5765.2025.08.016

Abstract

Abstract: PANoptosis, a novel form of inflammatory programmed cell death, is regulated and activated by the PANoptosome complex and possesses the main characteristics of pyroptosis, apoptosis, and necroptosis. PANoptosis plays a self-defense role in viral, bacterial, and fungal infectious diseases, while it exacerbates disease damage in inflammatory diseases. This article summarizes the definition and molecular regulatory mechanisms of PANoptosis, explores the crosstalk and correlations among various forms of cell death, and elaborates on the mechanisms of PANoptosis in central nervous system diseases such as stroke, brain tumors, sepsis-related encephalopathy, and epilepsy, aiming to provide new ideas for the clinical treatment of central nervous system diseases.

Key words: PANoptosis; Pyroptosis; Apoptosis; Necroptosis; Central nervous system disease

摘要： 泛凋亡（PANoptosis）是一种全新的炎症性程序性细胞死亡形式，由泛凋亡体（PANoptosome）复合物调控并激活，具有细胞焦亡、凋亡和坏死性凋亡的主要特征。泛凋亡在病毒、细菌、真菌感染性疾病中发挥自我防御功能，在炎症性疾病中则加重疾病损伤。本文介绍泛凋亡的定义及分子调控机制，探讨多种细胞死亡形式的串扰和关联关系，阐述泛凋亡在卒中、脑肿瘤、脓毒症相关性脑病、癫痫等中枢神经系统疾病中的作用机制，旨在为中枢神经系统疾病的临床治疗提供新思路。

关键词: 泛凋亡; 焦亡; 凋亡; 坏死性凋亡; 中枢神经系统疾病

CLC Number:

LIU Jia, LIU Xuemei. Research Progress on PANoptosis and Central Nervous System Diseases[J]. Chinese Journal of Stroke, 2025, 20(8): 1058-1065.

刘嘉, 刘雪梅. 泛凋亡与中枢神经系统疾病的研究进展[J]. 中国卒中杂志, 2025, 20(8): 1058-1065.

References

[1] GALLUZZI L，VITALE I，AARONSON S A，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.
[2] TUO Q Z，ZHANG S T，LEI P. Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications[J]. Med Res Rev，2022，42（1）：259-305.
[3] LIU L P，WANG D，WONG K S L，et al. Stroke and stroke care in China：huge burden，significant workload，and a national priority[J]. Stroke，2011，42（12）：3651-3654.
[4] WANG Y Q，KANNEGANTI T D. From pyroptosis，apoptosis and necroptosis to PANoptosis：a mechanistic compendium of programmed cell death pathways[J/OL]. Comput Struct Biotechnol J，2021，19：4641-4657[2025-02-16]. https://doi.org/10.1016/j.csbj.2021.07.038.
[5] MALIREDDI R K S，KESAVARDHANA S，KANNEGANTI T D. ZBP1 and TAK1：master regulators of NLRP3 inflammasome/pyroptosis，apoptosis，and necroptosis（PAN-optosis）[J/OL]. Front Cell Infect Microbiol，2019，9：406[2025-02-16]. https://doi.org/10.3389/fcimb.2019.00406.
[6] 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.
[7] QI Z H，ZHU L L，WANG K K，et al. PANoptosis：emerging mechanisms and disease implications[J/OL].
Life Sci，2023，333：122158[2025-02-16]. https://doi.org/10.1016/j.lfs.2023.122158.
[8] CHRISTGEN S，ZHENG M，KESAVARDHANA S，et al. Identification of the PANoptosome：a molecular platform triggering pyroptosis，apoptosis，and necroptosis（PANoptosis）[J/OL]. Front Cell Infect Microbiol，2020，10：237[2025-02-16]. https://doi.org/10.3389/fcimb.2020.00237.
[9] SAMIR P，MALIREDDI R K S，KANNEGANTI T D. The PANoptosome：a deadly protein complex driving pyroptosis，apoptosis，and necroptosis（PANoptosis）[J/OL]. Front Cell Infect Microbiol，2020，10：238[2025-02-16]. https://doi.org/10.3389/fcimb.2020.00238.
[10] HAO Y，YANG B，YANG J K，et al. ZBP1：a powerful innate immune sensor and double-edged sword in host immunity[J/OL]. Int J Mol Sci，2022，23（18）：10224[2025-02-16]. https://doi.org/10.3390/ijms231810224.
[11] KARKI R，SUNDARAM B，SHARMA B R，et al. ADAR1 restricts ZBP1-mediated immune response and PANoptosis to promote tumorigenesis[J/OL]. Cell Rep，2021，37（3）：109858[2025-02-16]. https://doi.org/10.1016/j.celrep.2021.109858.
[12] KARKI R，KANNEGANTI T D. PANoptosome signaling and therapeutic implications in infection：central role for ZBP1 to activate the inflammasome and PANoptosis[J/OL]. Curr Opin Immunol，2023，83：102348[2025-02-16]. https://doi.org/10.1016/j.coi.2023.102348.
[13] LEE S，KARKI R，WANG Y Q，et al. AIM2 forms a complex with pyrin and ZBP1 to drive PANoptosis and host defence[J]. Nature，2021，597（7876）：415-419.
[14] SHARMA B R，KARKI R，KANNEGANTI T D. Role of AIM2 inflammasome in inflammatory diseases，cancer and infection[J]. Eur J Immunol，2019，49（11）：1998-2011.
[15] ZHANG W Z Q，ZHU C L，LIAO Y，et al. Caspase-8 in inflammatory diseases：a potential therapeutic target[J/OL]. Cell Mol Biol Lett，2024，29（1）：130[2025-02-16]. https://doi.org/10.1186/s11658-024-00646-x.
[16] PLACE D E，LEE S，KANNEGANTI T D. PANoptosis in microbial infection[J/OL]. Curr Opin Microbiol，2021，59：42-49[2025-02-16]. https://doi.org/10.1016/j.mib.2020.07.012.
[17] SHEN L A，GAN Q Y，YANG Y C，et al. Mitophagy in cerebral ischemia and ischemia/reperfusion injury[J/OL]. Front Aging Neurosci，2021，13：687246[2025-02-16]. https://doi.org/10.3389/fnagi.2021.687246.
[18] ZHANG Q，JIA M，WANG Y F，et al. Cell death mechanisms in cerebral ischemia-reperfusion injury[J]. Neurochem Res，2022，47（12）：3525-3542.
[19] YAN W T，YANG Y D，HU X M，et al. Do pyroptosis，apoptosis，and necroptosis（PANoptosis）exist in cerebral ischemia？Evidence from cell and rodent studies[J]. Neural Regen Res，2022，17（8）：1761-1768.
[20] SHE R N，LIU D H，LIAO J，et al. Mitochondrial dysfunctions induce PANoptosis and ferroptosis in cerebral ischemia/reperfusion injury：from pathology to therapeutic potential[J/OL]. Front Cell Neurosci，2023，17：1191629[2025-02-16]. https://doi.org/10.3389/fncel.2023.1191629.
[21] LAN Z W，TAN F B，HE J L，et al. Curcumin-primed olfactory mucosa-derived mesenchymal stem cells mitigate cerebral ischemia/reperfusion injury-induced neuronal PANoptosis by modulating microglial polarization[J/OL]. Phytomedicine，2024，129：155635[2025-02-16]. https://doi.org/10.1016/j.phymed.2024.155635.
[22] ZHANG Y，KHAN S，LIU Y，et al. Modes of brain cell death following intracerebral hemorrhage[J/OL]. Front Cell Neurosci，2022，16：799753[2025-02-16]. https://doi.org/10.3389/fncel.2022.799753.
[23] DUAN J J，YUAN W，JIANG E Y，et al. PGAM5 promotes RIPK1-PANoptosome activity by phosphorylating and activating RIPK1 to mediate PANoptosis after subarachnoid hemorrhage in rats[J/OL]. Exp Neurol，2025，384：115072[2025-06-20]. https://doi.org/10.1016/j.expneurol.2024.115072.
[24] GU L G，CHEN H L，GENG R X，et al. Endothelial pyroptosis-driven microglial activation in choroid plexus mediates neuronal apoptosis in hemorrhagic stroke rats[J/OL]. Neurobiol Dis，2024，201：106695[2025-02-16]. https://doi.org/10.1016/j.nbd.2024.106695.
[25] WU Y，XU Y，SUN J S，et al. Inhibiting RIPK1-driven neuroinflammation and neuronal apoptosis mitigates brain injury following experimental subarachnoid hemorrhage[J/OL]. Exp Neurol，2024，374：114705[2025-02-16]. https://doi.org/10.1016/j.expneurol.2024.114705.
[26] JIANG T，YU J T，TAN L. Novel disease-modifying therapies for Alzheimer’s disease[J]. J Alzheimers Dis，2012，31（3）：475-492.
[27] WANG W X，LU J C，PAN N Y，et al. Identification of early Alzheimer’s disease subclass and signature genes based on PANoptosis genes[J/OL]. Front Immunol，2024，15：1462003[2025-02-16]. https://doi.org/10.3389/fimmu.2024.1462003.
[28] ZHANG E D，DAI F Q. Diagnostic model for Alzheimer’s disease based on PANoptosis-related genes[J]. J Alzheimers Dis，2024，97（2）：813-828.
[29] DONG Y，YU H Q，LI X Q，et al. Hyperphosphorylated Tau mediates neuronal death by inducing necroptosis and inflammation in Alzheimer’s disease[J/OL]. J Neuroinflammation，2022，19：205[2025-02-16]. https://doi.org/10.1186/s12974-022-02567-y.
[30] LIU H J，YOU M C，YANG H，et al. Exploring the molecular characterization of PANoptosis-related genes with features of immune dysregulation in Alzheimer’s disease based on bulk and single-nuclei RNA sequencing[J/OL]. Metab Brain Dis，2025，40（1）：109[2025-02-16]. https://doi.org/10.1007/s11011-025-01540-x.
[31] SARESELLA M，LA ROSA F，PIANCONE F，et al. The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer’s disease[J/OL]. Mol Neurodegener，2016，11：23[2025-02-16]. https://doi.org/10.1186/s13024-016-0088-1.
[32] LAPOINTE S，PERRY A，BUTOWSKI N A. Primary brain tumours in adults[J]. Lancet，2018，392（10145）：432-446.
[33] MALIREDDI R K S，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.
[34] CAI Y H，XIAO H，XUE S S，et al. Integrative analysis of immunogenic PANoptosis and experimental validation of cinobufagin-induced activation to enhance glioma immunotherapy[J/OL]. J Exp Clin Cancer Res，2025，44：35[2025-02-16]. https://doi.org/10.1186/s13046-025-03301-1.
[35] JIANG M X，QI L，LI L S，et al. Caspase-8：a key protein of cross-talk signal way in“PANoptosis”in cancer[J]. Int J Cancer，2021，149（7）：1408-1420.
[36] SONG J J，XU Z K，FAN Q C，et al. The PANoptosis-related signature indicates the prognosis and tumor immune infiltration features of gliomas[J/OL]. Front Mol Neurosci，2023，16：1198713[2025-02-16]. https://doi.org/10.3389/fnmol.2023.1198713.
[37] GOFTON T E，YOUNG G B. Sepsis-associated encephalopathy[J]. Nat Rev Neurol，2012，8（10）：557-566.
[38] ZHOU R X，YING J J，QIU X，et al. A new cell death program regulated by toll-like receptor 9 through p38 mitogen-activated protein kinase signaling pathway in a neonatal rat model with sepsis associated encephalopathy[J]. Chin Med J（Engl），2022，135（12）：1474-1485.
[39] YANG L，LI Z，XU Z J，et al. Protective effects of cannabinoid type 2 receptor activation against microglia overactivation and neuronal pyroptosis in sepsis-associated encephalopathy[J/OL]. Neuroscience，2022，493：99-108[2025-02-16]. https://doi.org/10.1016/j.neuroscience.2022.04.011.
[40] FAN Z M，MA H W，LI Y，et al. Neuronal MD2 induces long-term mental impairments in septic mice by facilitating necroptosis and apoptosis[J/OL]. Front Pharmacol，2022，13：884821[2025-02-16]. https://doi.org/10.3389/fphar.2022.884821.
[41] XIA L，LIU L，CAI Y Y，et al. Inhibition of gasdermin D-mediated pyroptosis attenuates the severity of seizures and astroglial damage in kainic acid-induced epileptic mice[J/OL]. Front Pharmacol，2021，12：751644[2025-02-16]. https://doi.org/10.3389/fphar.2021.751644.
[42] WANG X Y，YU X M，LI Y J，et al. ATF5 attenuates apoptosis in hippocampal neurons with seizures evoked by Mg2+-free medium via regulating mitochondrial unfolded protein response[J]. Neurochem Res，2023，48（1）：62-71.
[43] HUANG W Y，LAI Y L，LIU K H，et al. TNFα-mediated necroptosis in brain endothelial cells as a potential mechanism of increased seizure susceptibility in mice following systemic inflammation[J/OL]. J Neuroinflammation，2022，19：29[2025-02-16]. https://doi.org/10.1186/s12974-022-02406-0.
[44] LIU Y Y，CHANG Y J，JIANG X F，et al. Analysis of the role of PANoptosis in seizures via integrated bioinformatics analysis and experimental validation[J/OL]. Heliyon，2024，10（4）：e26219[2025-02-16]. https://doi.org/10.1016/j.heliyon.2024.e26219.
[45] 陈江玮，刁丽梅，姚春园，等. 泛凋亡在癫痫的发病机制中的作用和潜在机制[J]. 中国医药导报，2024，21（24）：53-57.
CHEN J W，DIAO L M，YAO C Y，et al. Role and potential mechanisms of PANoptosis in the pathogenesis of epilepsy[J]. China Medical Herald，2024，21（24）：53-57.