Hepatocellular carcinoma(HCC),a highly aggressive liver cancer,poses a large medical care burden worldwide.The prognosis of patients with HCC is poor,owing to recurrence and metastasis after common treatment methods.T...Hepatocellular carcinoma(HCC),a highly aggressive liver cancer,poses a large medical care burden worldwide.The prognosis of patients with HCC is poor,owing to recurrence and metastasis after common treatment methods.Therefore,identifying new targets to eliminate HCC cells is critical for treatment of HCC without recurrence.PANoptosis,a novel inflammatory cell death pathway,has become an intensively investigated area in recent years.The concept of PANoptosis has brought new hope for HCC therapy,given recent evidence implicating this form of programmed cell death in cancer progression,prognosis,and resistance to chemotherapy and immunotherapy.Despite increasing reviews describing the role of PANoptosis in various cancer types,to our knowledge,no systematic review has examined the implications of PANoptosis in HCC.Therefore,we sought to provide the first systematic review of the regulatory mechanisms and therapeutic potential of PANoptosis in HCC.We summarize recent progress in exploration of the role of PANoptosis in HCC,particularly regulation of the HCC tumor microenvironment by PANoptosis.Finally,we highlight the potential of PANoptosis-based diagnostic and therapeutic strategies for HCC.展开更多
Background Follicular atresia significantly impairs female fertility and hastens reproductive senescence.Apoptosis of granulosa cells is the primary cause of follicular atresia.Pyroptosis and necroptosis,as additional...Background Follicular atresia significantly impairs female fertility and hastens reproductive senescence.Apoptosis of granulosa cells is the primary cause of follicular atresia.Pyroptosis and necroptosis,as additional forms of pro-grammed cell death,have been reported in mammalian cells.However,the understanding of pyroptosis and necrop-tosis pathways in granulosa cells during follicular atresia remains unclear.This study explored the effects of pro-grammed cell death in granulosa cells on follicular atresia and the underlying mechanisms.Results The results revealed that granulosa cells undergo programmed cell death including apoptosis,pyroptosis,and necroptosis during follicular atresia.For the first time,we identified the formation of a PANoptosome com-plex in porcine granulosa cells.This complex was initially identified as being composed of ZBP1,RIPK3,and RIPK1,and is recruited through the RHIM domain.Additionally,we demonstrated that caspase-6 is activated and cleaved,interacting with RIPK3 as a component of the PANoptosome.Heat stress may exacerbate the activation of the PANop-tosome,leading to programmed cell death in granulosa cells.Conclusions Our data identified the formation of a PANoptosome complex that promoted programmed cell death in granulosa cells during the process of follicular atresia.These findings provide new insights into the molecular mechanisms underlying follicular atresia.展开更多
PANoptosis has been shown to play important pathophysiological roles,particularly in cancer.This review summarizes the composition and functions of PANoptosis and its associated PANoptosomes,including the ZBP1,RIPK1,A...PANoptosis has been shown to play important pathophysiological roles,particularly in cancer.This review summarizes the composition and functions of PANoptosis and its associated PANoptosomes,including the ZBP1,RIPK1,AIM2,and NLRP12-PANoptosomes.Predictive models based on PANoptosis markers have been developed to guide personalized treatment strategies,highlighting novel therapeutic targets.Research into compounds that modulate PANoptosis pathways is ongoing,with the aim of increasing cancer treatment efficacy and addressing challenges such as drug resistance and immune evasion.This review also summarizes innovative PANoptosis-related prognostic gene signature models and compounds that modulate PANoptosis pathways.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
基金supported by the National Natural Science Foundation of China (Grant No. 82460461)Medical Subject Leader of Yunnan Province (General Surgery)(Grant No.D-2024029)+4 种基金Yunnan Fundamental Research Project for Excellent Young Scholars (Grant No. 202401AW070003)Young and Mid-aged Academic and Technical Leader Reserve Talent Program of Yunnan Province (Grant No. 202205AC160063)Beijing Bethune Charitable Foundation (Grant No. STLKY0089)Top Talent Project of Kunming Medical University-Yang KeKunming Medical University Innovative Program for Postgraduate (Grant No. 2024S305).
文摘Hepatocellular carcinoma(HCC),a highly aggressive liver cancer,poses a large medical care burden worldwide.The prognosis of patients with HCC is poor,owing to recurrence and metastasis after common treatment methods.Therefore,identifying new targets to eliminate HCC cells is critical for treatment of HCC without recurrence.PANoptosis,a novel inflammatory cell death pathway,has become an intensively investigated area in recent years.The concept of PANoptosis has brought new hope for HCC therapy,given recent evidence implicating this form of programmed cell death in cancer progression,prognosis,and resistance to chemotherapy and immunotherapy.Despite increasing reviews describing the role of PANoptosis in various cancer types,to our knowledge,no systematic review has examined the implications of PANoptosis in HCC.Therefore,we sought to provide the first systematic review of the regulatory mechanisms and therapeutic potential of PANoptosis in HCC.We summarize recent progress in exploration of the role of PANoptosis in HCC,particularly regulation of the HCC tumor microenvironment by PANoptosis.Finally,we highlight the potential of PANoptosis-based diagnostic and therapeutic strategies for HCC.
基金National Key Research and Development Program of China(2022YFD1300405)National Natural Science Foundation of China(32202671)Open project of State Key Laboratory of Animal Biotech Breeding(Grant No.2024SKLAB6-5).
文摘Background Follicular atresia significantly impairs female fertility and hastens reproductive senescence.Apoptosis of granulosa cells is the primary cause of follicular atresia.Pyroptosis and necroptosis,as additional forms of pro-grammed cell death,have been reported in mammalian cells.However,the understanding of pyroptosis and necrop-tosis pathways in granulosa cells during follicular atresia remains unclear.This study explored the effects of pro-grammed cell death in granulosa cells on follicular atresia and the underlying mechanisms.Results The results revealed that granulosa cells undergo programmed cell death including apoptosis,pyroptosis,and necroptosis during follicular atresia.For the first time,we identified the formation of a PANoptosome com-plex in porcine granulosa cells.This complex was initially identified as being composed of ZBP1,RIPK3,and RIPK1,and is recruited through the RHIM domain.Additionally,we demonstrated that caspase-6 is activated and cleaved,interacting with RIPK3 as a component of the PANoptosome.Heat stress may exacerbate the activation of the PANop-tosome,leading to programmed cell death in granulosa cells.Conclusions Our data identified the formation of a PANoptosome complex that promoted programmed cell death in granulosa cells during the process of follicular atresia.These findings provide new insights into the molecular mechanisms underlying follicular atresia.
基金This study was supported by the National Natural Science Foundation of China(82273963)the 2023 Annual Graduate Students Innovation Fund from Tianjin University of Traditional Chinese Medicine(YJSKC-20231015)the 2022 Annual Graduate Students Innovation Fund from the School of Integrative Medicine,Tianjin University of Traditional Chinese Medicine(ZXYCXLX202211).
文摘PANoptosis has been shown to play important pathophysiological roles,particularly in cancer.This review summarizes the composition and functions of PANoptosis and its associated PANoptosomes,including the ZBP1,RIPK1,AIM2,and NLRP12-PANoptosomes.Predictive models based on PANoptosis markers have been developed to guide personalized treatment strategies,highlighting novel therapeutic targets.Research into compounds that modulate PANoptosis pathways is ongoing,with the aim of increasing cancer treatment efficacy and addressing challenges such as drug resistance and immune evasion.This review also summarizes innovative PANoptosis-related prognostic gene signature models and compounds that modulate PANoptosis pathways.
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.
