靶向组蛋白翻译后修饰调控细胞焦亡治疗骨关节炎的研究进展*

doi:10.3870/j.issn.1672-0741.25.07.048

摘要/Abstract

摘要： 骨关节炎是一种以关节软骨退行性病变为主要病理特征的慢性骨关节疾病。当前的临床治疗主要着眼于延缓疾病进展和控制临床症状,然而在促进软骨再生与修复方面仍面临挑战。近年研究表明,细胞焦亡在骨关节炎发病机制中发挥重要作用,通过NLRP3炎症小体激活和IL-1β等促炎因子释放,加剧关节炎症反应和软骨破坏。该综述系统阐述了蛋白翻译后修饰在调控细胞焦亡中的分子机制,重点关注泛素化、磷酸化、乙酰化和SUMO化等修饰通过动态调控NLRP3炎症小体组装及Gasdermin蛋白活化,调节细胞焦亡过程的分子机制。从而为深入理解骨关节炎发病机制和治疗策略提供新的理论视角。

关键词: 骨关节炎, 翻译后修饰, 细胞焦亡, 乙酰化修饰, 泛素化修饰

Abstract: Osteoarthritis is a chronic bone and joint disease characterized primarily by the degenerative changes of articular cartilage.Current clinical treatments primarily focus on delaying disease progression and managing clinical symptoms;however,challenges remain in promoting cartilage regeneration and repair.Recent studies have indicated that pyroptosis plays a significant role in the pathogenesis of osteoarthritis.It exacerbates joint inflammatory responses and cartilage destruction by activating the NLRP3 inflammasome and releasing pro-inflammatory cytokines such as IL-1β.This review systematically elaborates on the molecular mechanisms by which post-translational modifications regulate pyroptosis.It focuses on how modifications such as ubiquitination,phosphorylation,acetylation,and SUMOylation dynamically regulate the assembly of the NLRP3 inflammasome and the activation of Gasdermin proteins,thereby modulating the process of pyroptosis.This aims to provide a new theoretical perspective for a deeper understanding of the pathogenesis of osteoarthritis and its treatment strategies.

Key words: osteoarthritis, post-translational modifications, pyroptosis, acetylation modification, ubiquitination modification

中图分类号:

R684.3

牛朝阳, 曹玉净. 靶向组蛋白翻译后修饰调控细胞焦亡治疗骨关节炎的研究进展^*[J]. 华中科技大学学报（医学版）, 2026, 55(2): 296-301.

Niu Chaoyang, Cao Yujing. Research Advances in Targeting Protein Post-Translational Modifications to Regulate Pyroptosis for Osteoarthritis Therapy[J]. Acta Medicinae Universitatis Scientiae et Technologiae Huazhong, 2026, 55(2): 296-301.

参考文献

[1] Yao Q,Wu X,Tao C,et al.Osteoarthritis:Pathogenic signaling pathways and therapeutic targets[J].Signal Transduct Target Ther,2023,8(1):56.
[2] Quicke J G,Conaghan P G,Corp N,et al.Osteoarthritis year in review 2021:epidemiology & therapy[J].Osteoarthritis Cartilage,2022,30(2):196-206.
[3] Ri-Wen,Yang Y H,Zhang T N,et al.Targeting epigenetic and post-translational modifications regulating pyroptosis for the treatment of inflammatory diseases[J].Pharmacol Res,2024,203:107182.
[4] Lee J M,Hammarén H M,Savitski M M,et al.Control of protein stability by post-translational modifications[J].Nat Commun,2023,14(1):201.
[5] Zhang R N,Jing Z Q,Zhang L,et al.Epigenetic regulation of pyroptosis in cancer:Molecular pathogenesis and targeting strategies[J].Cancer Lett,2023,575:216413.
[6] Malik A,Kanneganti T D.Inflammasome activation and assembly at a glance[J].J Cell Sci,2017,130(23):3955-3963.
[7] Feng S,Fox D,Man S M.Mechanisms of gasdermin family members in inflammasome signaling and cell death[J].J Mol Biol,2018,430(18 Pt B):3068-3080.
[8] Cornut M,Bourdonnay E,Henry T.Transcriptional regulation of inflammasomes[J].Int J Mol Sci,2020,21(21):8087.
[9] Xue W,Cui D,Qiu Y.Research progress of pyroptosis in Alzheimer's disease[J].Front Mol Neurosci,2022,15:872471.
[10] Man S M,Karki R,Kanneganti T D.Molecular mechanisms and functions of pyroptosis,inflammatory caspases and inflammasomes in infectious diseases[J].Immunol Rev,2017,277(1):61-75.
[11] Aglietti R A,Estevez A,Gupta A,et al.GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes[J].Proc Natl Acad Sci USA,2016,113(28):7858-7863.
[12] Zhou Z,He H,Wang K,et al.Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells[J].Science,2020,368(6494):eaaz7548.
[13] Liu Y,Fang Y,Chen X,et al.Gasdermin E-mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome[J].Sci Immunol,2020,5(43):eaax7969.
[14] An S,Hu H,Li Y,et al.Pyroptosis plays a role in osteoarthritis[J].Aging Dis,2020,11(5):1146-1157.
[15] Zhang L,Xing R,Huang Z,et al.Inhibition of synovial macrophage pyroptosis alleviates synovitis and fibrosis in knee osteoarthritis[J].Mediators Inflamm,2019,2019:2165918.
[16] Gong H,Zhong H,Cheng L,et al.Post-translational protein lactylation modification in health and diseases:A double-edged sword[J].J Transl Med,2024,22(1):41.
[17] Huang L,Li F,Ye L,et al.Epigenetic regulation of embryonic ectoderm development in stem cell differentiation and transformation during ontogenesis[J].Cell Prolif,2023,56(4):e13413.
[18] Jennings E Q,Fritz K S,Galligan J J.Biochemical genesis of enzymatic and non-enzymatic post-translational modifications[J].Mol Aspects Med,2022,86:101053.
[19] Ge M M,Chen N,Zhou Y Q,et al.Galectin-3 in microglia-mediated neuroinflammation:Implications for central nervous system diseases[J].Curr Neuropharmacol,2022,20(11):2066-2080.
[20] Liu J,Cheng Y,Zheng M,et al.Targeting the ubiquitination/deubiquitination process to regulate immune checkpoint pathways[J].Signal Transduct Target Ther,2021,6(1):28.
[21] Song H,Liu B,Huai W,et al.The E3 ubiquitin ligase TRIM31 attenuates NLRP3 inflammasome activation by promoting proteasomal degradation of NLRP3[J].Nat Commun,2016,7:13727.
[22] Guo Y,Li L,Xu T,et al.HUWE1 mediates inflammasome activation and promotes host defense against bacterial infection[J].J Clin Invest,2020,130(12):6301-6316.
[23] Ren G,Zhang X,Xiao Y,et al.ABRO1 promotes NLRP3 inflammasome activation through regulation of NLRP3 deubiquitination[J].EMBO J,2019,38(6):e100376.
[24] Bednash J S,Johns F,Patel N,et al.The deubiquitinase STAMBP modulates cytokine secretion through the NLRP3 inflammasome[J].Cell Signal,2021,79:109859.
[25] Lin Y,Jiang S,Yao Y,et al.Posttranslational modification in bone homeostasis and osteoporosis[J].MedComm,2025,6(4):e70159.
[26] Song N,Liu Z S,Xue W,et al.NLRP3 phosphorylation is an essential priming event for inflammasome activation[J].Mol Cell,2017,68(1):185-197.e6.
[27] Zhu K,Jin X,Chi Z,et al.Priming of NLRP3 inflammasome activation by Msn kinase MINK1 in macrophages[J].Cell Mol Immunol,2021,18(10):2372-2382.
[28] Gavrilin M A,Prather E R,Vompe A D,et al.cAbl kinase regulates inflammasome activation and pyroptosis via ASC phosphorylation[J].J Immunol,2021,206(6):1329-1336.
[29] Tanishita Y,Sekiya H,Inohara N,et al.Listeria toxin promotes phosphorylation of the inflammasome adaptor ASC through Lyn and Syk to exacerbate pathogen expansion[J].Cell Rep,2022,38(8):110414.
[30] Rogers C,Erkes D A,Nardone A,et al.Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation[J].Nat Commun,2019,10(1):1689.
[31] Drazic A,Myklebust L M,Ree R,et al.The world of protein acetylation[J].Biochim Biophys Acta,2016,1864(10):1372-1401.
[32] Guan C,Huang X,Yue J,et al.SIRT3-mediated deacetylation of NLRC4 promotes inflammasome activation[J].Theranostics,2021,11(8):3981-3995.
[33] Zhang A,Pan Y,Wang H,et al.Excessive processing and acetylation of OPA1 aggravate age-related hearing loss via the dysregulation of mitochondrial dynamics[J].Aging Cell,2024,23(4):e14091.
[34] Yao F,Jin Z,Zheng Z,et al.HDAC11 promotes both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways causing pyroptosis via ERG in vascular endothelial cells[J].Cell Death Discov,2022,8(1):112.
[35] Liu H,Craig S E L,Molchanov V,et al.SUMOylation in skeletal development,homeostasis,and disease[J].Cells,2022,11(17):2710.
[36] Barry R,John S W,Liccardi G,et al.SUMO-mediated regulation of NLRP3 modulates inflammasome activity[J].Nat Commun,2018,9(1):3001.
[37] Shi Y,Li X,Xu W,et al.SUMOylation regulates GSDMD stability and pyroptosis[J].Int Immunopharmacol,2025,149:114187.
[38] Xiao Y,Zhao C,Tai Y,et al.STING mediates hepatocyte pyroptosis in liver fibrosis byepigenetically activating the NLRP3 inflammasome[J].Redox Biol,2023,62:102691.
[39] Anwar M U,van der Goot F G.Refining S-acylation:Structure,regulation,dynamics,and therapeutic implications[J].J Cell Biol,2023,222(11):e202307103.
[40] Zhang N,Yang Y,Xu D.Emerging roles of palmitoylation in pyroptosis[J].Trends Cell Biol,2025,35(6):500-514.
[41] Chiu L Y,Huang D Y,Lin W W.PARP-1 regulates inflammasome activity by poly-ADP-ribosylation of NLRP3 and interaction with TXNIP in primary macrophages[J].Cell Mol Life Sci,2022,79(2):108.
[42] Zhang X J,Shang K,Pu Y K,et al.Leojaponin inhibits NLRP3 inflammasome activation through restoration of autophagy via upregulating RAPTOR phosphorylation[J].J Ethnopharmacol,2021,278:114322.
[43] Kwak S B,Koppula S,In E J,et al.Artemisia extract suppresses NLRP3 and AIM2 inflammasome activation by inhibition of ASC phosphorylation[J].Mediators Inflamm,2018,2018:6054069.
[44] Pan H,Lin Y,Dou J,et al.Wedelolactone facilitates Ser/Thr phosphorylation of NLRP3 dependent on PKA signalling to block inflammasome activation and pyroptosis[J].Cell Prolif,2020,53(9):e12868.
[45] Chen Y,Liu Y,Jiang K,et al.Linear ubiquitination of LKB1 activates AMPK pathway to inhibit NLRP3 inflammasome response and reduce chondrocyte pyroptosis in osteoarthritis[J].J Orthop Translat,2022,39:1-11.
[46] Xu H,Xu B.BMSC-derived exosomes ameliorate osteoarthritis by inhibiting pyroptosis of cartilage via delivering miR-326 targeting HDAC3 and STAT1/NF-κB p65 to chondrocytes[J].Mediators Inflamm,2021,2021:9972805.

靶向组蛋白翻译后修饰调控细胞焦亡治疗骨关节炎的研究进展^*

Research Advances in Targeting Protein Post-Translational Modifications to Regulate Pyroptosis for Osteoarthritis Therapy

PDF

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 8

编辑推荐

Metrics

本文评价

[1]	刘倩文, 叶樱泽, 佘科鹏, 李美红, 罗放, 张玥. VX-765通过抑制细胞焦亡改善脑卒中后中枢痛^*[J]. 华中科技大学学报（医学版）, 2026, 55(2): 149-154.
[2]	王玉娟, 贾永龙, 刘婧, 许宏斌, 强胜林, 黄凯, 陈环环, 赵玲. 消定膏干预NLRP3/NF-κB/Caspase-1通路治疗急性闭合性软组织损伤的作用机制[J]. 华中科技大学学报（医学版）, 2025, 54(3): 328-334.
[3]	叶子丰, 邝高艳, 院一蔚, 邱礼国, 许晓彤, 文志, 卢敏. 线粒体自噬对骨性关节炎的影响[J]. 华中科技大学学报（医学版）, 2024, 53(6): 858-864.
[4]	柯有力, 罗东, 刘旭, 别磊. lncRNAGAS5调控miR-452-5p/Mcl-1通路对急性肺损伤大鼠肺组织细胞焦亡的影响[J]. 华中科技大学学报（医学版）, 2024, 53(5): 621-628.
[5]	王强, 冯靖, 谭章勇, 杨晓江. 吴茱萸碱调节NF-κB通路对膝骨关节炎巨噬细胞极化的影响[J]. 华中科技大学学报（医学版）, 2024, 53(4): 444-451.
[6]	王浩, 郭文文, 吕兴华. 细胞焦亡在肾缺血再灌注损伤中的研究进展[J]. 华中科技大学学报（医学版）, 2024, 53(2): 275-280.
[7]	李浩, 何承建, 张天臣. 强骨通痹胶囊对大鼠骨关节炎炎症因子的影响及作用机制[J]. 华中科技大学学报（医学版）, 2023, 52(6): 828-833.
[8]	付钰, 古丽玲, 罗昌禄, 吴晓勇, 李宝杰, 夏景富. 苗药验方通过Wnt/β-catenin信号通路减轻家兔骨关节炎软骨细胞的损伤[J]. 华中科技大学学报（医学版）, 2023, 52(1): 48-53.