坏死性凋亡在肝纤维化中的作用

吴旋; 李晖; 董海舰; 杨希坤; 王凯鑫

doi:10.12449/JCH240827

坏死性凋亡在肝纤维化中的作用

DOI: 10.12449/JCH240827

吴旋^{1, 2},
李晖^1, , ,,
董海舰^{1, 2},
杨希坤^{1, 2},
王凯鑫^{1, 2}

1.
成都中医药大学附属医院中心实验室，成都 610072
2.
成都中医药大学临床医学院，成都 610072

基金项目:

国家自然科学基金面上项目 (82274323)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：吴旋负责撰写论文；董海舰、杨希坤、王凯鑫参与查找文献，修改论文；李晖负责拟定写作思路，指导论文撰写并最后定稿。

详细信息

通信作者:
李晖， 1400124746@qq.com （ORCID： 0000-0002-5919-1396）

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出版历程
- 收稿日期: 2024-01-08
- 录用日期: 2024-03-13
- 出版日期: 2024-08-25

The role of necroptosis in liver fibrosis

Xuan WU^{1, 2},
Hui LI^{1
, ,
,},
Haijian DONG^{1, 2},
Xikun YANG^{1, 2},
Kaixin WANG^{1, 2}

1.
Central Laboratory，The Affiliated Hospital of Chengdu University of Traditional Chinese Medicine，Chengdu 610072，China
2.
School of Clinical Medicine，Chengdu University of Traditional Chinese Medicine，Chengdu 610072，China

Research funding:

General Project of National Natural Science Foundation of China (82274323)

More Information

Corresponding author: LI Hui， 1400124746@qq.com （ORCID： 0000-0002-5919-1396）

摘要

摘要: 肝纤维化作为各种慢性肝病向肝硬化发展的关键环节，影响其预后与转归。坏死性凋亡是一种新型的程序性细胞死亡模式，已被证明在多种疾病的病理生理中发挥重要作用，同样也被认为是改善肝纤维化的潜在靶点。不同类型的肝内细胞（包括肝细胞、肝星状细胞、肝巨噬细胞及肝窦内皮细胞）发生坏死性凋亡，可对肝纤维化发挥促进或抑制作用，本文着重阐述上述作用机制，并讨论靶向坏死性凋亡介导的肝纤维化的治疗策略。
- 肝纤维化 /
- 坏死性凋亡 /
- 肝星状细胞
Abstract: As a crucial link in the progression of various chronic liver diseases to liver cirrhosis， liver fibrosis affects the prognosis and outcome of chronic liver diseases. Necrotosis is a novel pattern of programmed cell death （PCD）， and studies have shown that it plays an important role in the pathophysiology of various diseases and is considered a potential target for improving liver fibrosis. Necroptosis of various types of intrahepatic cells （including hepatocytes， hepatic stellate cells， liver macrophages， and hepatic sinusoidal endothelial cells） can promote or inhibit liver fibrosis. This article elaborates on the above mechanisms and discusses the therapeutic strategies for targeting liver fibrosis mediated by necroptosis.
- Hepatic Fibrosis /
- Necroptosis /
- Hepatic Stellate Cells

HTML全文

表 1 肝内细胞坏死性凋亡与肝纤维化的关系

Table 1. Relationship between intrahepatic cell necroptosis and liver fibrosis

肝内细胞类型	发生坏死性凋亡后对肝纤维化的影响	主要作用机制	治疗思路
肝细胞	促进	促进促炎因子DAMP释放，诱导HSC活化	抑制其坏死性凋亡
HSC	抑制	直接抑制HSC活化	靶向促进其发生坏死性凋亡
M1巨噬细胞	抑制	促进促炎因子DAMP释放，诱导HSC活化	靶向促进其发生坏死性凋亡
M2巨噬细胞	促进	吞噬死亡肝细胞，清除促炎因子，抑制HSC活化	抑制其坏死性凋亡
肝窦内皮细胞	促进	调节肝脏内环境能力受损，促进HSC活化	抑制其坏死性凋亡

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参考文献(40)

[1]	YANG X, LI Q, LIU WT, et al. Mesenchymal stromal cells in hepatic fibrosis/cirrhosis: From pathogenesis to treatment[J]. Cell Mol Immunol, 2023, 20( 6): 583- 599. DOI: 10.1038/s41423-023-00983-5.
[2]	HUANG DQ, TERRAULT NA, TACKE F, et al. Global epidemiology of cirrhosis-aetiology, trends and predictions[J]. Nat Rev Gastroenterol Hepatol, 2023, 20( 6): 388- 398. DOI: 10.1038/s41575-023-00759-2.
[3]	ORNOS ED, MURILLO KJ, ONG JP. Liver diseases: Perspective from the Philippines[J]. Ann Hepatol, 2023, 28( 3): 101085. DOI: 10.1016/j.aohep.2023.101085.
[4]	ZHANG WB, FAN WL, GUO J, et al. Osmotic stress activates RIPK3/MLKL-mediated necroptosis by increasing cytosolic pH through a plasma membrane Na⁺/H⁺ exchanger[J]. Sci Signal, 2022, 15( 734): eabn5881. DOI: 10.1126/scisignal.abn5881.
[5]	GALLUZZI L, KEPP O, CHAN FKM, et al. Necroptosis: Mechanisms and relevance to disease[J]. Annu Rev Pathol, 2017, 12: 103- 130. DOI: 10.1146/annurev-pathol-052016-100247.
[6]	ANNIBALDI A, MEIER P. Checkpoints in TNF-induced cell death: Implications in inflammation and cancer[J]. Trends Mol Med, 2018, 24( 1): 49- 65. DOI: 10.1016/j.molmed.2017.11.002.
[7]	TING AT, BERTRAND MJM. More to life than NF-κB in TNFR1 signaling[J]. Trends Immunol, 2016, 37( 8): 535- 545. DOI: 10.1016/j.it.2016.06.002.
[8]	ZHANG YY, SU SS, ZHAO SB, et al. RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome[J]. Nat Commun, 2017, 8: 14329. DOI: 10.1038/ncomms14329.
[9]	WEI S, ZHOU HM, WANG Q, et al. RIP3 deficiency alleviates liver fibrosis by inhibiting ROCK1-TLR4-NF-κB pathway in macrophages[J]. FASEB J, 2019, 33( 10): 11180- 11193. DOI: 10.1096/fj.201900752R.
[10]	ROYCHOWDHURY S, MCCULLOUGH RL, SANZ-GARCIA C, et al. Receptor interacting protein 3 protects mice from high-fat diet-induced liverinjury[J]. Hepatology, 2016, 64( 5): 1518- 1533. DOI: 10.1002/hep.28676.
[11]	WU XQ, POULSEN KL, SANZ-GARCIA C, et al. MLKL-dependent signaling regulates autophagic flux in a murine model of non-alcohol-associated fatty liver and steatohepatitis[J]. J Hepatol, 2020, 73( 3): 616- 627. DOI: 10.1016/j.jhep.2020.03.023.
[12]	MAJDI A, AOUDJEHANE L, RATZIU V, et al. Inhibition of receptor-interacting protein kinase 1 improves experimental non-alcoholic fatty liver disease[J]. J Hepatol, 2020, 72( 4): 627- 635. DOI: 10.1016/j.jhep.2019.11.008.
[13]	SCHUPPAN D, SURABATTULA R, WANG XY. Determinants of fibrosis progression and regression in NASH[J]. J Hepatol, 2018, 68( 2): 238- 250. DOI: 10.1016/j.jhep.2017.11.012.
[14]	KOSCHEL J, NISHANTH G, JUST S, et al. OTUB1 prevents lethal hepatocyte necroptosis through stabilization of c-IAP1 during murine liver inflammation[J]. Cell Death Differ, 2021, 28( 7): 2257- 2275. DOI: 10.1038/s41418-021-00752-9.
[15]	MOHAMMED S, THADATHIL N, SELVARANI R, et al. Necroptosis contributes to chronic inflammation and fibrosis in aging liver[J]. Aging Cell, 2021, 20( 12): e13512. DOI: 10.1111/acel.13512.
[16]	ZHANG BC, LI MD, YIN RN, et al. O-GlcNAc transferase suppresses necroptosis and liver fibrosis[J]. JCI Insight, 2019, 4( 21): e127709. DOI: 10.1172/jci.insight.127709.
[17]	LIU Q, LEI XH, CAO ZY, et al. TRPM8 deficiency attenuates liver fibrosis through S100A9-HNF4α signaling[J]. Cell Biosci, 2022, 12( 1): 58. DOI: 10.1186/s13578-022-00789-4.
[18]	ZHOU J, ZHAO Y, GUO YJ, et al. A rapid juvenile murine model of nonalcoholic steatohepatitis(NASH): Chronic intermittent hypoxia exacerbates Western diet-induced NASH[J]. Life Sci, 2021, 276: 119403. DOI: 10.1016/j.lfs.2021.119403.
[19]	GUERRA S, MOCCIARO G, GASTALDELLI A. Adipose tissue insulin resistance and lipidome alterations as the characterizing factors of non-alcoholic steatohepatitis[J]. Eur J Clin Invest, 2022, 52( 3): e13695. DOI: 10.1111/eci.13695.
[20]	GUO R, JIA XH, DING ZB, et al. Loss of MLKL ameliorates liver fibrosis by inhibiting hepatocyte necroptosis and hepatic stellate cell activation[J]. Theranostics, 2022, 12( 11): 5220- 5236. DOI: 10.7150/thno.71400.
[21]	HUANG J, LI RB, WANG CB. Molecular mechanism of UPRmt in ameliorating alcohol-induced hepatocyte necroptosis[J]. Acad J Chin PLA Med Sch, 2023, 44( 6): 700- 707. DOI: 10.3969/j.issn.2095-5227.2023.06.020. 黄嘉, 李芮冰, 王成彬. UPRmt改善乙醇诱导的肝细胞坏死性凋亡的分子机制研究[J]. 解放军医学院学报, 2023, 44( 6): 700- 707. DOI: 10.3969/j.issn.2095-5227.2023.06.020.
[22]	JIA Y, WANG FX, GUO Q, et al. Curcumol induces RIPK1/RIPK3 complex-dependent necroptosis via JNK1/2-ROS signaling in hepatic stellate cells[J]. Redox Biol, 2018, 19: 375- 387. DOI: 10.1016/j.redox.2018.09.007.
[23]	OH JH, SAEED WK, KIM HY, et al. Hepatic stellate cells activate and avoid death under necroptosis stimuli: Hepatic fibrosis during necroptosis[J]. J Gastroenterol Hepatol, 2023, 38( 12): 2206- 2214. DOI: 10.1111/jgh.16368.
[24]	NOVO E, MARRA F, ZAMARA E, et al. Overexpression of Bcl-2 by activated human hepatic stellate cells: Resistance to apoptosis as a mechanism of progressive hepatic fibrogenesis in humans[J]. Gut, 2006, 55( 8): 1174- 1182. DOI: 10.1136/gut.2005.082701.
[25]	LU CF, XU WX, ZHANG F, et al. Study of Dihydroartemisinin on inducing necroptosis through activating Nrf2 in hepatic stellate cells in vitro[J]. China J Tradit Chin Med Pharm, 2016, 31( 5): 1919- 1925. 陆春风, 许文萱, 张峰, 等. 双氢青蒿素通过激活Nrf2促进肝星状细胞坏死性凋亡的研究[J]. 中华中医药杂志, 2016, 31( 5): 1919- 1925.
[26]	SUN SM, HUAN S, LI ZH, et al. Curcumol alleviates liver fibrosis by inducing endoplasmic reticulum stress-mediated necroptosis of hepatic stellate cells through Sirt1/NICD pathway[J]. Peer J, 2022, 10: e13376. DOI: 10.7717/peerj.13376.
[27]	KISSELEVA T, BRENNER D. Molecular and cellular mechanisms of liver fibrosis and its regression[J]. Nat Rev Gastroenterol Hepatol, 2021, 18( 3): 151- 166. DOI: 10.1038/s41575-020-00372-7.
[28]	HU MY, WANG Y, LIU ZS, et al. Hepatic macrophages act as a central hub for relaxin-mediated alleviation of liver fibrosis[J]. Nat Nanotechnol, 2021, 16( 4): 466- 477. DOI: 10.1038/s41565-020-00836-6.
[29]	WU XQ, FAN XD, MCMULLEN MR, et al. Macrophage-derived MLKL in alcohol-associated liver disease: Regulation of phagocytosis[J]. Hepatology, 2023, 77( 3): 902- 919. DOI: 10.1002/hep.32612.
[30]	GAUTHERON J, VUCUR M, REISINGER F, et al. A positive feedback loop between RIP3 and JNK controls non-alcoholic steatohepatitis[J]. EMBO Mol Med, 2014, 6( 8): 1062- 1074. DOI: 10.15252/emmm.201403856.
[31]	NI Y, LI JM, LIU MK, et al. Pathological process of liver sinusoidal endothelial cells in liver diseases[J]. World J Gastroenterol, 2017, 23( 43): 7666- 7677. DOI: 10.3748/wjg.v23.i43.7666.
[32]	POISSON J, LEMOINNE S, BOULANGER C, et al. Liver sinusoidal endothelial cells: Physiology and role in liver diseases[J]. J Hepatol, 2017, 66( 1): 212- 227. DOI: 10.1016/j.jhep.2016.07.009.
[33]	LAFOZ E, RUART M, ANTON A, et al. The endothelium as a driver of liver fibrosis and regeneration[J]. Cells, 2020, 9( 4): 929. DOI: 10.3390/cells9040929.
[34]	YAN ML, LI H, XU SY, et al. Targeting endothelial necroptosis disrupts profibrotic endothelial-hepatic stellate cells crosstalk to alleviate liver fibrosis in nonalcoholic steatohepatitis[J]. Int J Mol Sci, 2023, 24( 14): 11313. DOI: 10.3390/ijms241411313.
[35]	ZHENG F, DEVOOGDT N, SPARKES A, et al. Monitoring liver macrophages using nanobodies targeting Vsig4: Concanavalin A induced acute hepatitis as paradigm[J]. Immunobiology, 2015, 220( 2): 200- 209. DOI: 10.1016/j.imbio.2014.09.018.
[36]	LI JX, FENG JM, WANG Y, et al. The B-Raf(V600E) inhibitor dabrafenib selectively inhibits RIP3 and alleviates acetaminophen-induced liver injury[J]. Cell Death Dis, 2014, 5( 6): e1278. DOI: 10.1038/cddis.2014.241.
[37]	WANG SG, NI HM, DORKO K, et al. Increased hepatic receptor interacting protein kinase 3 expression due to impaired proteasomal functions contributes to alcohol-induced steatosis and liver injury[J]. Oncotarget, 2016, 7( 14): 17681- 17698. DOI: 10.18632/oncotarget.6893.
[38]	GÜNTHER C, HE GW, KREMER AE, et al. The pseudokinase MLKL mediates programmed hepatocellular necrosis independently of RIPK3 during hepatitis[J]. J Clin Invest, 2016, 126( 11): 4346- 4360. DOI: 10.1172/JCI87545.
[39]	LIM EJ, KHOBAR KE, CHIN R, et al. Hepatitis C virus-induced hepatocyte cell death and protection by inhibition of apoptosis[J]. J Gen Virol, 2014, 95( Pt 10): 2204- 2215. DOI: 10.1099/vir.0.065862-0.
[40]	HUANG LJ, MAO DW, ZHANG RZ, et al. Research advances in traditional Chinese medicine regulation of programmed cell death in intervening against hepatic fibrosis[J]. J Clin Hepatol, 2024, 40( 1): 161- 168. DOI: 10.12449/JCH240127. 黄良江, 毛德文, 张荣臻, 等. 中医药调控程序性细胞死亡干预肝纤维化的研究进展[J]. 临床肝胆病杂志, 2024, 40( 1): 161- 168. DOI: 10.12449/JCH240127.