坏死性凋亡在代谢相关脂肪性肝病中的作用机制及相关靶向治疗

刘翔; 龚志建; 刘娅卿; 黄家豪; 翟静雅; 崔贺贺; 邢宇锋

doi:10.12449/JCH260925

坏死性凋亡在代谢相关脂肪性肝病中的作用机制及相关靶向治疗

DOI: 10.12449/JCH260925

1.
广州中医药大学第四临床医学院，广东深圳 518000
2.
深圳市中医院肝病科，广东深圳 518000

基金项目:

深圳市科技计划项目 (JCYJ20250604145810014);

深圳市科技计划项目 (JCYJ20240813152444057);

深圳市医疗卫生三名工程项目 (SZZYSM202411013)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：邢宇锋、刘翔负责设计论文框架，起草论文；龚志建、刘娅卿负责数据收集；黄家豪、翟静雅负责论文撰写；崔贺贺负责复审；邢宇锋指导撰写并最后定稿。

详细信息

通信作者:
邢宇锋， yufeng000729@163.com （ORCID： 0000-0001-6762-3788）

计量
- 文章访问数: 14
- HTML全文浏览量: 7
- PDF下载量: 0
- 被引次数: 0
出版历程
- 收稿日期: 2025-12-11
- 录用日期: 2026-02-26
- 出版日期: 2026-09-25

Mechanism of action of necroptosis in metabolic dysfunction-associated fatty liver disease and related targeted therapies

1.
The Fourth Clinical Medical College，Guangzhou University of Chinese Medicine，Shenzhen，Guangdong 518000，China
2.
Department of Hepatology，Shenzhen Traditional Chinese Medicine Hospital，Shenzhen，Guangdong 518000，China

Research funding:

Shenzhen Science and Technology Plan Project (JCYJ20250604145810014);

Shenzhen Science and Technology Plan Project (JCYJ20240813152444057);

Shenzhen Medical and Health Three Famous Project (SZZYSM202411013)

More Information

Corresponding author: Xing Yufeng， yufeng000729@163.com （ORCID： 0000-0001-6762-3788）

摘要

摘要: 代谢相关脂肪性肝病是全球范围内常见的慢性肝病，其发病率持续上升。传统的“双重打击”学说已逐渐被“多重打击”假说所取代，后者强调多种致病因素的协同作用。坏死性凋亡作为一种兼具坏死形态学特征和凋亡信号机制的炎症性死亡形式，其核心在于受体相互作用蛋白激酶1-受体相互作用蛋白激酶3-混合谱系激酶结构域样蛋白信号轴。该通路不仅直接诱导肝细胞死亡，通过释放损伤相关分子模式触发炎症反应和推动纤维化进程，还与肝脏的代谢重编程等密切相关。本综述旨在总结坏死性凋亡在代谢相关脂肪性肝病中的激活机制，对肝脏炎症、纤维化及代谢的影响，并探讨其治疗策略及应用前景。
- 坏死性凋亡 /
- 代谢相关脂肪性肝病 /
- 信号传导 /
- 治疗学
Abstract: Metabolic dysfunction-associated fatty liver disease is a common chronic liver disease worldwide， and its incidence rate continues to rise. The traditional “two-hit” theory has gradually been replaced by the “multiple-hit” hypothesis， which emphasizes the synergistic effect of multiple pathogenic factors. Necroptosis is an inflammatory form of death with both the morphological characteristics of necrosis and the signaling mechanism of apoptosis， and the core of necroptosis lies in the receptor-interacting protein kinase 1-receptor-interacting protein kinase 3-mixed lineage kinase domain-like pseudokinase signaling axis. This pathway directly leads to the death of hepatocytes， and it triggers an inflammatory response and promotes the fibrosis process by releasing damage-associated molecular patterns； the pathway is also closely associated with the metabolic reprogramming of the liver. This review summarizes the activation mechanism of necroptosis in metabolic dysfunction-associated fatty liver disease， analyzes its effect on liver inflammation， fibrosis， and metabolism， and explores its therapeutic strategies and application prospects.
- Necroptosis /
- Metabolic Dysfunction-Associated Fatty Liver Disease /
- Signal Transduction /
- Therapeutics

HTML全文

注： TNF，肿瘤坏死因子；TNFR1，肿瘤坏死因子受体1；TRADD，肿瘤坏死因子受体相关死亡结构域蛋白；RIPK1，受体相互作用蛋白激酶1；TRAF2，肿瘤坏死因子受体相关因子2；cIAP1/2，细胞凋亡抑制蛋白1/2；FADD，肿瘤坏死因子受体超家族6相关死亡域蛋白；caspase-8，胱天蛋白酶8；FLIP，细胞caspase-8样抑制蛋白；RIPK3，受体相互作用蛋白激酶3；MLKL，混合谱系激酶结构域样蛋白。

图 1 TNF-α介导的坏死性凋亡

Figure 1. TNF-α mediated necroptosis diagram

下载: 全尺寸图片幻灯片

参考文献(48)

[1]	Younossi Z M, Kalligeros M, Henry L. Epidemiology of metabolic dysfunction-associated steatotic liver disease[J]. Clin Mol Hepatol, 2025, 31: S32- S50. DOI: 10.3350/cmh.2024.0431.
[2]	Guo Z W, Wu D J, Mao R H, et al. Global burden of MAFLD, MAFLD related cirrhosis and MASH related liver cancer from 1990 to 2021[J]. Sci Rep, 2025, 15( 1): 7083. DOI: 10.1038/s41598-025-91312-5.
[3]	Hagström H, Shang Y, Hegmar H, et al. Natural history and progression of metabolic dysfunction-associated steatotic liver disease[J]. Lancet Gastroenterol Hepatol, 2024, 9( 10): 944- 956. DOI: 10.1016/S2468-1253(24)00193-6.
[4]	Tilg H, Adolph T E, Moschen A R. Multiple parallel hits hypothesis in nonalcoholic fatty liver disease: Revisited after a decade[J]. Hepatology, 2021, 73( 2): 833- 842. DOI: 10.1002/hep.31518.
[5]	Shojaie L, Iorga A, Dara L. Cell death in liver diseases: A review[J]. Int J Mol Sci, 2020, 21( 24): 9682. DOI: 10.3390/ijms21249682.
[6]	Bertheloot D, Latz E, Franklin B S. Necroptosis, pyroptosis and apoptosis: An intricate game of cell death[J]. Cell Mol Immunol, 2021, 18( 5): 1106- 1121. DOI: 10.1038/s41423-020-00630-3.
[7]	Zheng Hong, Su Wenjun, Jiang Chunlei. Inflammatory mechanism of central nervous system diseases mediated by necrotizing apoptosis[J]. Clin J Med Offic, 2024, 52( 7): 762- 765, 768. 郑红, 苏文君, 蒋春雷. 坏死性凋亡介导中枢神经系统疾病炎性机制[J]. 临床军医杂志, 2024, 52( 7): 762- 765, 768.
[8]	Chen Yiting, Wang Pei. Roles of non-apoptotic programmed cell death in metabolic-associated fatty liver disease[J]. Acad J Second Mil Med Univ, 2023, 44( 6): 657- 665. DOI: 10.16781/j.CN31-2187/R.20220745. 陈奕婷, 王培. 非凋亡程序性细胞死亡在代谢相关脂肪性肝病中的作用[J]. 海军军医大学学报, 2023, 44( 6): 657- 665. DOI: 10.16781/j.CN31-2187/R.20220745.
[9]	Afonso M B, Rodrigues P M, Mateus-Pinheiro M, et al. RIPK3 acts as a lipid metabolism regulator contributing to inflammation and carcinogenesis in non-alcoholic fatty liver disease[J]. Gut, 2021, 70( 12): 2359- 2372. DOI: 10.1136/gutjnl-2020-321767.
[10]	Afonso M B, David J C, Alves M I, et al. Intricate interplay between cell metabolism and necroptosis regulation in metabolic dysfunction-associated steatotic liver disease: A narrative review[J]. Metabolism, 2024, 158: 155975. DOI: 10.1016/j.metabol.2024.155975.
[11]	Soták M, Clark M, Suur B E, et al. Inflammation and resolution in obesity[J]. Nat Rev Endocrinol, 2025, 21( 1): 45- 61. DOI: 10.1038/s41574-024-01047-y.
[12]	Schwabe R F, Luedde T. Apoptosis and necroptosis in the liver: A matter of life and death[J]. Nat Rev Gastroenterol Hepatol, 2018, 15( 12): 738- 752. DOI: 10.1038/s41575-018-0065-y.
[13]	Gautheron J, Gores G J, Rodrigues C M P. Lytic cell death in metabolic liver disease[J]. J Hepatol, 2020, 73( 2): 394- 408. DOI: 10.1016/j.jhep.2020.04.001.
[14]	Chen P, Yao L C, Yuan M Q, et al. Mitochondrial dysfunction: A promising therapeutic target for liver diseases[J]. Genes Dis, 2024, 11( 3): 101115. DOI: 10.1016/j.gendis.2023.101115.
[15]	Lu W, Sun J H, Yoon J S, et al. Mitochondrial protein PGAM5 regulates mitophagic protection against cell necroptosis[J]. PLoS One, 2016, 11( 1): e0147792. DOI: 10.1371/journal.pone.0147792.
[16]	She Lang, Peng Jun. Phosphoglycerate mutase 5 and necroptosis[J]. Chin J Pathophysiol, 2016, 32( 2): 377- 380. DOI: 10.3969/j.issn.1000-4718.2016.02.031. 佘浪, 彭军. 磷酸甘油酸变位酶5与坏死样凋亡[J]. 中国病理生理杂志, 2016, 32( 2): 377- 380. DOI: 10.3969/j.issn.1000-4718.2016.02.031.
[17]	Deragon M A, McCaig W D, Truong P V, et al. Mitochondrial trafficking of MLKL, Bak/Bax, and Drp1 is mediated by RIP1 and ROS which leads to decreased mitochondrial membrane integrity during the hyperglycemic shift to necroptosis[J]. Int J Mol Sci, 2023, 24( 10): 8609. DOI: 10.3390/ijms24108609.
[18]	Gomes Torres A C M B, Leite N, Tureck L V, et al. Association between Toll-like receptors(TLR) and NOD-like receptor(NLR) polymorphisms and lipid and glucose metabolism[J]. Gene, 2019, 685: 211- 221. DOI: 10.1016/j.gene.2018.11.065.
[19]	He S D, Liang Y Q, Shao F, et al. Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3-mediated pathway[J]. Proc Natl Acad Sci U S A, 2011, 108( 50): 20054- 20059. DOI: 10.1073/pnas.1116302108.
[20]	Wu P, Zhang M Y, Webster N J G. Alternative RNA splicing in fatty liver disease[J]. Front Endocrinol, 2021, 12: 613213. DOI: 10.3389/fendo.2021.613213.
[21]	Riebeling T, Kunzendorf U, Krautwald S. The role of RHIM in necroptosis[J]. Biochem Soc Trans, 2022, 50( 4): 1197- 1205. DOI: 10.1042/BST20220535.
[22]	Thapa R J, Nogusa S, Chen P R, et al. Interferon-induced RIP1/RIP3-mediated necrosis requires PKR and is licensed by FADD and caspases[J]. Proc Natl Acad Sci U S A, 2013, 110( 33): E3109- E3118. DOI: 10.1073/pnas.1301218110.
[23]	Ding Z C, Wang R, Li Y H, et al. MLKL activates the cGAS-STING pathway by releasing mitochondrial DNA upon necroptosis induction[J]. Mol Cell, 2025, 85( 13): 2610- 2625. DOI: 10.1016/j.molcel.2025.06.005.
[24]	Place D E, Samir P, Malireddi R S, et al. Integrated stress response restricts macrophage necroptosis[J]. Life Sci Alliance, 2022, 5( 1): e202101260. DOI: 10.26508/lsa.202101260.
[25]	Tu T J, Alba M M, Datta A A, et al. Hepatic macrophage mediated immune response in liver steatosis driven carcinogenesis[J]. Front Oncol, 2022, 12: 958696. DOI: 10.3389/fonc.2022.958696.
[26]	Luedde T, Schwabe R F. NF-κB in the liver: Linking injury, fibrosis and hepatocellular carcinoma[J]. Nat Rev Gastroenterol Hepatol, 2011, 8( 2): 108- 118. DOI: 10.1038/nrgastro.2010.213.
[27]	Zhang J B, Zhang Q R, Jin Q, et al. Sestrin2 maintains hepatic immune homeostasis and redox balance partially via inhibiting RIPK3-mediated necroptosis in metabolic dysfunction-associated steatohepatitis[J]. Mol Metab, 2024, 80: 101865. DOI: 10.1016/j.molmet.2023.101865.
[28]	Nakadate K, Saitoh H, Sakaguchi M, et al. Advances in understanding lipopolysaccharide-mediated hepatitis: Mechanisms and pathological features[J]. Curr Issues Mol Biol, 2025, 47( 2): 79. DOI: 10.3390/cimb47020079.
[29]	Mohammed S, Nicklas E H, Thadathil N, et al. Role of necroptosis in chronic hepatic inflammation and fibrosis in a mouse model of increased oxidative stress[J]. Free Radic Biol Med, 2021, 164: 315- 328. DOI: 10.1016/j.freeradbiomed.2020.12.449.
[30]	Davies M J. Myeloperoxidase-derived oxidation: Mechanisms of biological damage and its prevention[J]. J Clin Biochem Nutr, 2011, 48( 1): 8- 19. DOI: 10.3164/jcbn.11-006FR.
[31]	Guo R, Jia X H, Ding Z B, 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.
[32]	Oh J H, Saeed W K, Kim H Y, 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.
[33]	He Y H, Jiang J L, Ou L L, et al. Impaired RelA signaling and lipid metabolism dysregulation in hepatocytes: Driving forces in the progression of metabolic dysfunction-associated steatotic liver disease[J]. Cell Death Discov, 2025, 11: 49. DOI: 10.1038/s41420-025-02312-3.
[34]	Posey K A, Clegg D J, Printz R L, et al. Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet[J]. Am J Physiol Endocrinol Metab, 2009, 296( 5): E1003- E1012. DOI: 10.1152/ajpendo.90377.2008.
[35]	Amer A E, Ghoneim H A, Abdelaziz R R, et al. L-carnitine attenuates autophagic flux, apoptosis, and necroptosis in rats with dexamethasone-induced non-alcoholic steatohepatitis[J]. BMC Pharmacol Toxicol, 2024, 25( 1): 102. DOI: 10.1186/s40360-024-00820-z.
[36]	Tan S X, Zhao J, Sun Z Y, et al. Hepatocyte-specific TAK1 deficiency drives RIPK1 kinase-dependent inflammation to promote liver fibrosis and hepatocellular carcinoma[J]. Proc Natl Acad Sci U S A, 2020, 117( 25): 14231- 14242. DOI: 10.1073/pnas.2005353117.
[37]	Weisel K, Scott N E, Tompson D J, et al. Randomized clinical study of safety, pharmacokinetics, and pharmacodynamics of RIPK1 inhibitor GSK2982772 in healthy volunteers[J]. Pharmacol Res Perspect, 2017, 5( 6): e00365. DOI: 10.1002/prp2.365.
[38]	Bai Y L, Qiao Y J, Li M M, et al. RIPK1 inhibitors: A key to unlocking the potential of necroptosis in drug development[J]. Eur J Med Chem, 2024, 265: 116123. DOI: 10.1016/j.ejmech.2024.116123.
[39]	Soday L, Seripracharat C, Gray J L, et al. Discovery and validation of a novel class of necroptosis inhibitors targeting RIPK1[J]. ACS Chem Biol, 2025, 20( 7): 1527- 1543. DOI: 10.1021/acschembio.5c00112.
[40]	Yu Qian, Bian Shu, Zhang Yuting, et al. Role of RIPK3 in LPS/D-GalN induced acute liver failure[J]. J Med Mol Biol, 2024, 21( 3): 196- 202. DOI: 10.3870/j.issn.1672-8009.2024.03.002. 于倩, 边姝, 张钰婷, 等. RIPK3在LPS/D-GalN诱导急性肝衰竭中的作用研究[J]. 医学分子生物学杂志, 2024, 21( 3): 196- 202. DOI: 10.3870/j.issn.1672-8009.2024.03.002.
[41]	Mohammed S, Ohene-Marfo P, Jiang C, et al. Impact of Mlkl or Ripk3 deletion on age-associated liver inflammation, metabolic health, and lifespan[J]. Geroscience, 2025, 47( 3): 4465- 4483. DOI: 10.1007/s11357-025-01553-5.
[42]	Zhou X Y, Lin B, Chen W, et al. The brain protection of MLKL inhibitor necrosulfonamide against focal ischemia/reperfusion injury associating with blocking the nucleus and nuclear envelope translocation of MLKL and RIP3K[J]. Front Pharmacol, 2023, 14: 1157054. DOI: 10.3389/fphar.2023.1157054.
[43]	Oh J H, Park S, Hong E, et al. Novel inhibitor of mixed-lineage kinase domain-like protein: The antifibrotic effects of a necroptosis antagonist[J]. ACS Pharmacol Transl Sci, 2023, 6( 10): 1471- 1479. DOI: 10.1021/acsptsci.3c00131.
[44]	Hao Mingyue, Sun Linlin, Sheng Mingwei, et al. Berberine alleviates programmed necrosis of metabolic-associated fatty liver disease via activating Nrf2 pathway in mice[J]. Chin J Hepatol, 2022, 30( 2): 224- 229. DOI: 10.3760/cma.j.cn501113-20200910-00509. 郝明月, 孙琳琳, 盛明薇, 等. 小檗碱激活Nrf2通路减轻小鼠代谢相关脂肪性肝病程序性坏死[J]. 中华肝脏病杂志, 2022, 30( 2): 224- 229. DOI: 10.3760/cma.j.cn501113-20200910-00509.
[45]	Xu M X, Ge C X, Qin Y T, et al. Activated TNF-α/RIPK3 signaling is involved in prolonged high fat diet-stimulated hepatic inflammation and lipid accumulation: Inhibition by dietary fisetin intervention[J]. Food Funct, 2019, 10( 3): 1302- 1316. DOI: 10.1039/c8fo01615a.
[46]	Matboli M, Saad M, Ahmed M F, et al. Febuxostat alleviate metabolic dysfunction-associated steatohepatitis in rat model via targeting inflammation, cell death, and intestinal barrier dysfunction[J]. Biomed Pharmacother, 2025, 187: 118086. DOI: 10.1016/j.biopha.2025.118086.
[47]	Wu X Q, Nagy L E, Gautheron J. Mediators of necroptosis: From cell death to metabolic regulation[J]. EMBO Mol Med, 2024, 16( 2): 219- 237. DOI: 10.1038/s44321-023-00011-z.
[48]	Zhao J N, Hu Y Y, Peng J H. Targeting programmed cell death in metabolic dysfunction-associated fatty liver disease(MAFLD): A promising new therapy[J]. Cell Mol Biol Lett, 2021, 26( 1): 17. DOI: 10.1186/s11658-021-00254-z.