PANoptosis is a newly identified type of regulated cell death that consists of pyroptosis,apoptosis,and nec roptosis,which simultaneously occur during the pathophysiological process of infectious and inflammatory dise...PANoptosis is a newly identified type of regulated cell death that consists of pyroptosis,apoptosis,and nec roptosis,which simultaneously occur during the pathophysiological process of infectious and inflammatory diseases.Although our previous lite rature mining study suggested that PANoptosis might occur in neuronal ischemia/repe rfusion injury,little experimental research has been reported on the existence of PANoptosis.In this study,we used in vivo and in vitro retinal neuronal models of ischemia/repe rfusion injury to investigate whether PAN optosis-like cell death(simultaneous occurrence of pyroptosis,apo ptosis,and necroptosis)exists in retinal neuronal ischemia/repe rfusion injury.Our results showed that ischemia/repe rfusion injury induced changes in morphological features and protein levels that indicate PANoptosis-like cell death in retinal neurons both in vitro and in vivo.Ischemia/repe rfusion inju ry also significantly upregulated caspase-1,caspase-8,and NLRP3 expression,which are important components of the PANoptosome.These results indicate the existence of PANoptosis-like cell death in ischemia/reperfusion injury of retinal neurons and provide preliminary experimental evidence for future study of this new type of regulated cell death.展开更多
Hepatocellular carcinoma(HCC)is the most common fatal cancer worldwide,patients with HCC have a high mortality rate and poor prognosis.PANoptosis is a novel discovery of programmed cell death associated with cancer de...Hepatocellular carcinoma(HCC)is the most common fatal cancer worldwide,patients with HCC have a high mortality rate and poor prognosis.PANoptosis is a novel discovery of programmed cell death associated with cancer development.However,the role of PANoptosis in HCC remains obscure.In this study,we enrolled 274 PANoptosisrelated genes(PANRGs)and screened 8 genes to set up a prognostic model.A previous scoring system calculated PANscore was utilized to quantify the individual risk level of each HCC patient,and the reliability of the prognostic model has been validated in an external cohort.Nomogram constructed with PANscore and clinical characteristics were used to optimize individualized treatment for each patient.Single-cell analysis revealed a PANoptosis model associated with tumor immune cell infiltration,particularly natural killer(NK)cells.Further exploration of hub genes and assessment of the prognostic role of these 4 hub genes in HCC by quantitative real-time PCR(qRT-PCR)and immunohistochemistry(IHC).In conclusion,we evaluated a PANoptosis-based prognostic model as a potential prognostic biomarker for HCC patients.展开更多
Some scholars have recently developed the concept of PANoptosis in the study of infectious diseases where pyroptosis,apoptosis and necroptosis act in consort in a multimeric protein complex,PANoptosome.This allows all...Some scholars have recently developed the concept of PANoptosis in the study of infectious diseases where pyroptosis,apoptosis and necroptosis act in consort in a multimeric protein complex,PANoptosome.This allows all the components of PANoptosis to be regulated simultaneously.PANoptosis provides a new way to study the regulation of cell death,in that different types of cell death may be regulated at the same time.To test whether PANoptosis exists in diseases other than infectious diseases,we chose cerebral ischemia/reperfusion injury as the research model,collected articles researching cerebral ischemia/reperfusion from three major databases,obtained the original research data from these articles by bibliometrics,data mining and other methods,then integrated and analyzed these data.We selected papers that investigated at least two of the components of PANoptosis to check its occurrence in ischemia/reperfusion.In the cell model simulating ischemic brain injury,pyroptosis,apoptosis and necroptosis occur together and this phenomenon exists widely in different passage cell lines or primary neurons.Pyroptosis,apoptosis and necroptosis also occurred in rat and mouse models of ischemia/reperfusion injury.This confirms that PANoptosis is observed in ischemic brain injury and indicates that PANoptosis can be a target in the regulation of various central nervous system diseases.展开更多
Inflammasomes are important sentinels of innate immune defense;they sense pathogens and induce the cell death of infected cells,playing key roles in inflammation,development,and cancer.Several inflammasome sensors det...Inflammasomes are important sentinels of innate immune defense;they sense pathogens and induce the cell death of infected cells,playing key roles in inflammation,development,and cancer.Several inflammasome sensors detect and respond to specific pathogen-and damage-associated molecular patterns(PAMPs and DAMPs,respectively)by forming a multiprotein complex with the adapters ASC and caspase-1.During disease,cells are exposed to several PAMPs and DAMPs,leading to the concerted activation of multiple inflammasomes.However,the molecular mechanisms that integrate multiple inflammasome sensors to facilitate optimal host defense remain unknown.Here,we discovered that simultaneous inflammasome activation by multiple ligands triggered multiple types of programmed inflammatory cell death,and these effects could not be mimicked by treatment with a pure ligand of any single inflammasome.Furthermore,NLRP3,AIM2,NLRC4,and Pyrin were determined to be members of a large multiprotein complex,along with ASC,caspase-1,caspase-8,and RIPK3,and this complex drove PANoptosis.Furthermore,this multiprotein complex was released into the extracellular space and retained as multiple inflammasomes.Multiple extracellular inflammasome particles could induce inflammation after their engulfment by neighboring macrophages.Collectively,our findings define a previously unknown regulatory connection and molecular interaction between inflammasome sensors,which drives the assembly of a multiprotein complex that includes multiple inflammasome sensors and cell death regulators.The discovery of critical interactions among NLRP3,AIM2,NLRC4,and Pyrin represents a new paradigm in understanding the functions of these molecules in innate immunity and inflammasome biology as well as identifying new therapeutic targets for NLRP3-,AIM2-,NLRC4-and Pyrin-mediated diseases.展开更多
Regulated cell death(such as apoptosis,necroptosis,pyroptosis,autophagy,cuproptosis,ferroptosis,disulfidptosis)involves complex signaling pathways and molecular effectors,and has been proven to be an important regulat...Regulated cell death(such as apoptosis,necroptosis,pyroptosis,autophagy,cuproptosis,ferroptosis,disulfidptosis)involves complex signaling pathways and molecular effectors,and has been proven to be an important regulatory mechanism for regulating neuronal aging and death.However,excessive activation of regulated cell death may lead to the progression of aging-related diseases.This review summarizes recent advances in the understanding of seven forms of regulated cell death in age-related diseases.Notably,the newly identified ferroptosis and cuproptosis have been implicated in the risk of cognitive impairment and neurodegenerative diseases.These forms of cell death exacerbate disease progression by promoting inflammation,oxidative stress,and pathological protein aggregation.The review also provides an overview of key signaling pathways and crosstalk mechanisms among these regulated cell death forms,with a focus on ferroptosis,cuproptosis,and disulfidptosis.For instance,FDX1 directly induces cuproptosis by regulating copper ion valency and dihydrolipoamide S-acetyltransferase aggregation,while copper mediates glutathione peroxidase 4 degradation,enhancing ferroptosis sensitivity.Additionally,inhibiting the Xc-transport system to prevent ferroptosis can increase disulfide formation and shift the NADP^(+)/NADPH ratio,transitioning ferroptosis to disulfidptosis.These insights help to uncover the potential connections among these novel regulated cell death forms and differentiate them from traditional regulated cell death mechanisms.In conclusion,identifying key targets and their crosstalk points among various regulated cell death pathways may aid in developing specific biomarkers to reverse the aging clock and treat age-related neurodegenerative conditions.展开更多
Oncogenic KRAS reprograms pancreatic ductal adenocarcinoma(PDAC) cells to a state that is awfully resistant to apoptosis.An alternative coping strategy is to trigger a nonapoptotic cell death.Herein,a multi specific p...Oncogenic KRAS reprograms pancreatic ductal adenocarcinoma(PDAC) cells to a state that is awfully resistant to apoptosis.An alternative coping strategy is to trigger a nonapoptotic cell death.Herein,a multi specific platinum complex SEP was constructed by conjugating a quinone derivative seratrodast to a prodrug of cisplatin.Interestingly,SEP-treated KRAS-mutant PDAC cells showed the characteristics of pyroptosis,apoptosis and necroptosis,similar to PANoptosis(a newfound inflammatory cell death).Mechanistically,SEP could enter cancer cells effectively,then damage nuclear DNA,boost mitochondrial superoxide anion radicals and affect various signaling pathways related to redox homeostasis and tumor metabolism.To our best knowledge,SEP is the first metal complex,even small molecule,to elicit PANoptosis(pyroptosis,apoptosis and necroptosis) in cancer cells,providing a new strategy to overcome apoptotic resistance of KRAS-mutant PDAC.展开更多
Regulated cell death(RCD),including apoptosis,pyroptosis,necroptosis,and ferroptosis,is regulated by a series of evolutionarily conserved pathways,and is required for development and tissue homeostasis.Based on previo...Regulated cell death(RCD),including apoptosis,pyroptosis,necroptosis,and ferroptosis,is regulated by a series of evolutionarily conserved pathways,and is required for development and tissue homeostasis.Based on previous genetic and biochemical explorations of cell death subroutines,the characteristics of each are generally considered distinctive.However,recent in-depth studies noted the presence of crosstalk between the different forms of RCD;hence,the concept of PANoptosis appeared.Cancer,a complex genetic disease,is characterized by stepwise deregulation of cell apoptosis and proliferation,with significant morbidity and mortality globally.At present,studies on the different RCD pathways,as well as the intricate relationships between different cell death subroutines,mainly focus on infectious diseases,and their roles in cancer remain unclear.As cancers are characterized by dysregulated cell death and inflammatory responses,most current treatment strategies aim to selectively induce cell death via different RCD pathways in cancer cells.In this review,we describe five types of RCD pathways in detail with respect to tumorigenesis and cancer progression.The potential value of some of these key effector molecules in tumor diagnosis and therapeutic response has also been raised.We then review and highlight recent progress in cancer treatment based on PANoptosis and ferroptosis induced by small-molecule compounds,immune checkpoint inhibitors,and nanoparticles.Together,these findings may provide meaningful evidence to fill in the gaps between cancer pathogenesis and RCD pathways to develop better cancer therapeutic strategies.展开更多
基金supported by the National Natural Science Foundation of China,Nos.81772134,81971891,82172196,81571939(ail to KX)the Key Laboratory of Emergency and Trauma(Hainan Medical University)of Ministry of Education,No.KLET-202108(to KX)+1 种基金the Fundamental Research Funds for the Central Universities of Central South University of China,No.2020zzts218(to WTY)Hunan Provincial Innovation Foundation for Postgraduate of China,No.CX20200116(to WTY)。
文摘PANoptosis is a newly identified type of regulated cell death that consists of pyroptosis,apoptosis,and nec roptosis,which simultaneously occur during the pathophysiological process of infectious and inflammatory diseases.Although our previous lite rature mining study suggested that PANoptosis might occur in neuronal ischemia/repe rfusion injury,little experimental research has been reported on the existence of PANoptosis.In this study,we used in vivo and in vitro retinal neuronal models of ischemia/repe rfusion injury to investigate whether PAN optosis-like cell death(simultaneous occurrence of pyroptosis,apo ptosis,and necroptosis)exists in retinal neuronal ischemia/repe rfusion injury.Our results showed that ischemia/repe rfusion injury induced changes in morphological features and protein levels that indicate PANoptosis-like cell death in retinal neurons both in vitro and in vivo.Ischemia/repe rfusion inju ry also significantly upregulated caspase-1,caspase-8,and NLRP3 expression,which are important components of the PANoptosome.These results indicate the existence of PANoptosis-like cell death in ischemia/reperfusion injury of retinal neurons and provide preliminary experimental evidence for future study of this new type of regulated cell death.
基金This study was supported by grants from the Central Guidance on Local Science and Technology Development Fund of HeBei Province(226Z7705G)Hebei Natural Science Foundation(H2020206458,H2020206513 and H2022206552)+1 种基金Science and Technology Research Project of Colleges and Universities in Hebei Province(ZD2021074 and ZD2022143)2022 Introduction of Foreign Intellectual Property Project in Hebei Province(SWZYCYZ202001).
文摘Hepatocellular carcinoma(HCC)is the most common fatal cancer worldwide,patients with HCC have a high mortality rate and poor prognosis.PANoptosis is a novel discovery of programmed cell death associated with cancer development.However,the role of PANoptosis in HCC remains obscure.In this study,we enrolled 274 PANoptosisrelated genes(PANRGs)and screened 8 genes to set up a prognostic model.A previous scoring system calculated PANscore was utilized to quantify the individual risk level of each HCC patient,and the reliability of the prognostic model has been validated in an external cohort.Nomogram constructed with PANscore and clinical characteristics were used to optimize individualized treatment for each patient.Single-cell analysis revealed a PANoptosis model associated with tumor immune cell infiltration,particularly natural killer(NK)cells.Further exploration of hub genes and assessment of the prognostic role of these 4 hub genes in HCC by quantitative real-time PCR(qRT-PCR)and immunohistochemistry(IHC).In conclusion,we evaluated a PANoptosis-based prognostic model as a potential prognostic biomarker for HCC patients.
基金supported by the National Natural Science Foundation of China,Nos.81772134(to KX),81971891(to KX),82172196(to KX),81571939(to KX)the Fundamental Research Funds for the Central Universities of Central South University of China,No.2020zzts218,(to WTY)Hunan Provincial Innovation Foundation For Postgraduate of China,Nos.CX20200116(to WTY),CX20190139(to LSL).
文摘Some scholars have recently developed the concept of PANoptosis in the study of infectious diseases where pyroptosis,apoptosis and necroptosis act in consort in a multimeric protein complex,PANoptosome.This allows all the components of PANoptosis to be regulated simultaneously.PANoptosis provides a new way to study the regulation of cell death,in that different types of cell death may be regulated at the same time.To test whether PANoptosis exists in diseases other than infectious diseases,we chose cerebral ischemia/reperfusion injury as the research model,collected articles researching cerebral ischemia/reperfusion from three major databases,obtained the original research data from these articles by bibliometrics,data mining and other methods,then integrated and analyzed these data.We selected papers that investigated at least two of the components of PANoptosis to check its occurrence in ischemia/reperfusion.In the cell model simulating ischemic brain injury,pyroptosis,apoptosis and necroptosis occur together and this phenomenon exists widely in different passage cell lines or primary neurons.Pyroptosis,apoptosis and necroptosis also occurred in rat and mouse models of ischemia/reperfusion injury.This confirms that PANoptosis is observed in ischemic brain injury and indicates that PANoptosis can be a target in the regulation of various central nervous system diseases.
基金supported by the National Research Foundation of Korea(NRF)grant that was funded by the Korean government(MSIT)(2022R1C1C1007544 to SL)by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute(KHIDI)that was funded by the Ministry of Health&Welfare,Republic of Korea(HV22C015600 to SL)+2 种基金by grants from the National Institute of Health,Republic of Korea(2022-NI-072-00 to SL),by the Institute for Basic Science(IBS),Republic of Korea(IBS-R801-D9-A09 to SL)by a research fund from Ulsan National Institute of Science&Technology(UNIST)(1.220112.01,1.220107.01 to SL)by a grant from Yuhan Corporation(SL),by the National Research Foundation of Korea(NRF)and the Center for Women In Science,Engineering and Technology(WISET)grant that was funded by the Ministry of Science and ICT(MSIT)under the Program for Returners into R&D(to JL).
文摘Inflammasomes are important sentinels of innate immune defense;they sense pathogens and induce the cell death of infected cells,playing key roles in inflammation,development,and cancer.Several inflammasome sensors detect and respond to specific pathogen-and damage-associated molecular patterns(PAMPs and DAMPs,respectively)by forming a multiprotein complex with the adapters ASC and caspase-1.During disease,cells are exposed to several PAMPs and DAMPs,leading to the concerted activation of multiple inflammasomes.However,the molecular mechanisms that integrate multiple inflammasome sensors to facilitate optimal host defense remain unknown.Here,we discovered that simultaneous inflammasome activation by multiple ligands triggered multiple types of programmed inflammatory cell death,and these effects could not be mimicked by treatment with a pure ligand of any single inflammasome.Furthermore,NLRP3,AIM2,NLRC4,and Pyrin were determined to be members of a large multiprotein complex,along with ASC,caspase-1,caspase-8,and RIPK3,and this complex drove PANoptosis.Furthermore,this multiprotein complex was released into the extracellular space and retained as multiple inflammasomes.Multiple extracellular inflammasome particles could induce inflammation after their engulfment by neighboring macrophages.Collectively,our findings define a previously unknown regulatory connection and molecular interaction between inflammasome sensors,which drives the assembly of a multiprotein complex that includes multiple inflammasome sensors and cell death regulators.The discovery of critical interactions among NLRP3,AIM2,NLRC4,and Pyrin represents a new paradigm in understanding the functions of these molecules in innate immunity and inflammasome biology as well as identifying new therapeutic targets for NLRP3-,AIM2-,NLRC4-and Pyrin-mediated diseases.
基金supported by the Key Projects of Medical Science and Technology of Henan Province,No.SBGJ202002099(to JY)。
文摘Regulated cell death(such as apoptosis,necroptosis,pyroptosis,autophagy,cuproptosis,ferroptosis,disulfidptosis)involves complex signaling pathways and molecular effectors,and has been proven to be an important regulatory mechanism for regulating neuronal aging and death.However,excessive activation of regulated cell death may lead to the progression of aging-related diseases.This review summarizes recent advances in the understanding of seven forms of regulated cell death in age-related diseases.Notably,the newly identified ferroptosis and cuproptosis have been implicated in the risk of cognitive impairment and neurodegenerative diseases.These forms of cell death exacerbate disease progression by promoting inflammation,oxidative stress,and pathological protein aggregation.The review also provides an overview of key signaling pathways and crosstalk mechanisms among these regulated cell death forms,with a focus on ferroptosis,cuproptosis,and disulfidptosis.For instance,FDX1 directly induces cuproptosis by regulating copper ion valency and dihydrolipoamide S-acetyltransferase aggregation,while copper mediates glutathione peroxidase 4 degradation,enhancing ferroptosis sensitivity.Additionally,inhibiting the Xc-transport system to prevent ferroptosis can increase disulfide formation and shift the NADP^(+)/NADPH ratio,transitioning ferroptosis to disulfidptosis.These insights help to uncover the potential connections among these novel regulated cell death forms and differentiate them from traditional regulated cell death mechanisms.In conclusion,identifying key targets and their crosstalk points among various regulated cell death pathways may aid in developing specific biomarkers to reverse the aging clock and treat age-related neurodegenerative conditions.
基金supported by the National Natural Science Foundation of China (21731004,91953201,21907050,22107047)the Natural Science Foundation of Jiangsu Province (BK20202004)+1 种基金the Postdoctoral Research Funding Program of Jiangsu Province (003503)the Excellent Research Program of Nanjing University (ZYJH004)
文摘Oncogenic KRAS reprograms pancreatic ductal adenocarcinoma(PDAC) cells to a state that is awfully resistant to apoptosis.An alternative coping strategy is to trigger a nonapoptotic cell death.Herein,a multi specific platinum complex SEP was constructed by conjugating a quinone derivative seratrodast to a prodrug of cisplatin.Interestingly,SEP-treated KRAS-mutant PDAC cells showed the characteristics of pyroptosis,apoptosis and necroptosis,similar to PANoptosis(a newfound inflammatory cell death).Mechanistically,SEP could enter cancer cells effectively,then damage nuclear DNA,boost mitochondrial superoxide anion radicals and affect various signaling pathways related to redox homeostasis and tumor metabolism.To our best knowledge,SEP is the first metal complex,even small molecule,to elicit PANoptosis(pyroptosis,apoptosis and necroptosis) in cancer cells,providing a new strategy to overcome apoptotic resistance of KRAS-mutant PDAC.
基金Natural Science Foundation of China(No.82072689)the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(No.2020HXFH010)
文摘Regulated cell death(RCD),including apoptosis,pyroptosis,necroptosis,and ferroptosis,is regulated by a series of evolutionarily conserved pathways,and is required for development and tissue homeostasis.Based on previous genetic and biochemical explorations of cell death subroutines,the characteristics of each are generally considered distinctive.However,recent in-depth studies noted the presence of crosstalk between the different forms of RCD;hence,the concept of PANoptosis appeared.Cancer,a complex genetic disease,is characterized by stepwise deregulation of cell apoptosis and proliferation,with significant morbidity and mortality globally.At present,studies on the different RCD pathways,as well as the intricate relationships between different cell death subroutines,mainly focus on infectious diseases,and their roles in cancer remain unclear.As cancers are characterized by dysregulated cell death and inflammatory responses,most current treatment strategies aim to selectively induce cell death via different RCD pathways in cancer cells.In this review,we describe five types of RCD pathways in detail with respect to tumorigenesis and cancer progression.The potential value of some of these key effector molecules in tumor diagnosis and therapeutic response has also been raised.We then review and highlight recent progress in cancer treatment based on PANoptosis and ferroptosis induced by small-molecule compounds,immune checkpoint inhibitors,and nanoparticles.Together,these findings may provide meaningful evidence to fill in the gaps between cancer pathogenesis and RCD pathways to develop better cancer therapeutic strategies.
