肿瘤坏死因子-α介导的信号网络调控酒精性肝炎的研究新进展

doi:10.12092/j.issn.1009-2501.2026.07.012

摘要/Abstract

摘要：

酒精性肝炎（AH）是指长期过量饮酒，乙醇及其代谢物引起的肝脏免疫炎症性疾病，肿瘤坏死因子-α（TNF-α）对AH肝组织炎症细胞浸润、肝细胞肿大并发生脂肪变，汇管区纤维组织增生等肝组织炎症反应发挥关键的调控作用，故TNF-α调控AH的相关信号网络已成为近年来研究的新热点。本文从核转录因子-κB（NF-κB）、Toll样受体4（TLR4）、NOD样受体蛋白结构域相关蛋白3（NLRP3）炎性小体、丝裂原活化蛋白激酶（MAPK）以及信号转导与转录激活因子3（STAT3）等信号网络的角度，综述TNF-α调控AH的作用机制，为AH肝组织炎症反应机制研究以及新药研发提供理论依据。

关键词: 酒精性肝炎, 肿瘤坏死因子-α, 信号网络, 研究进展

Abstract:

Alcoholic hepatitis (AH) is an immunoin flammatory disease of the liver caused by long-term heavy drinking of ethanol and its metabolites. Tumor necrosis factor-α (TNF-α) plays a key regulatory role in the inflammatory response of liver tissue, such as inflammatory cell infiltration, hepatocyte hepatocyte enlargement with steatosis, and fibrous tissue hyperplasia in the confluent area during the process of AH. Therefore, TNF-α regulation of AH-related signaling networks has become a new research hotspot in recent years. This article reviews the mechanism of TNF-α in regulating alcoholic hepatitis from the perspective of signaling networks such as nuclear factor-kappaB (NF-κB), Toll-like receptor 4 (TLR4), NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome, mitogen-activated protein kinase (MAPK) as well as signal transducers and activators of transcription 3 (STAT3), to provide a theoretical basis for the study of the inflammatory response mechanism of AH liver tissue and the development of new drugs.

Key words: alcoholic hepatitis, tumor necrosis factor-α, signaling network, research progress

中图分类号:

R966

田蓓, 郭玫, 王志旺, 张悦, 全苹, 赵跃, 王琦玮, 朱昕宇, 邵晶. 肿瘤坏死因子-α介导的信号网络调控酒精性肝炎的研究新进展[J]. 中国临床药理学与治疗学, 2026, 31(7): 957-964.

Bei TIAN, Mei GUO, Zhiwang WANG, Yue ZHANG, Ping QUAN, Yue ZHAO, Qiwei WANG, Xinyu ZHU, Jing SHAO. New research progress of tumor necrosis factor-α signaling pathway regulating alcoholic hepatitis[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(7): 957-964.

图/表 2

参考文献 49

1	Enciu VT, Ologeanu PM, Constantinescu A, et al. Latest insights in alcohol-related liver disease and alcoholic hepatitis[J]. Rom J Intern Med, 2025, 63 (2): 97- 106.
2	Wang W, Liu M, Fu X, et al. Hydroxysafflor yellow A ameliorates alcohol-induced liver injury through PI3K/Akt and STAT3/NF-κB signaling pathways[J]. Phytomedicine, 2024, 132, 155814- 155814. doi: 10.1016/j.phymed.2024.155814
3	李丽, 刘艳, 陈静. 重症酒精性肝炎患者血清 TNF-α、IL-1β 表达与病情严重程度相关性分析[J]. 临床消化病杂志, 2022, 34 (4): 221- 225.
4	Shen H, Liangpunsakul S, Iwakiri Y, et al. Immunological mechanisms and emerging therapeutic targets in alcohol-associated liver disease[J]. Cell Mol Immunol, 2025, 22 (10): 1190- 1204. doi: 10.1038/s41423-025-01291-w
5	Chuyun Y, Wanting H, Jinqi T, et al. Pathogenic mechanisms and regulatory factors involved in alcoholic liver disease[J]. J Transl Med, 2023, 21 (1): 300- 300. doi: 10.1186/s12967-023-04166-8
6	Yuk MJ, Kim KJ, Kim SI, et al. TNF in human tuberculosis: A double-edged sword[J]. Immune Network, 2024, 24 (1): e4- e4. doi: 10.4110/in.2024.24.e4
7	García-Domínguez M. The role of TNF-α in neuropathic pain: An immunotherapeutic perspective[J]. Life, 2025, 15 (5): 785. doi: 10.3390/life15050785
8	Scarlata MGG, Colaci C, Scarcella M, et al. The role of cytokines in the pathogenesis and treatment of alcoholic liver disease[J]. Diseases (Basel, Switzerland), 2024, 12 (4): 69.
9	陈思韵, 冯钟文, 庞丽君, 等. 基于网络药理学探究积雪草酸抗酒精性肝炎的作用机制[J]. 中国药理学通报, 2021, 37 (8): 1145- 1151.
10	Hu Y, Wang Y, Li X, et al. Clostridium butyricum JJ100 and Lacticaseibacillus rhamnosus LR alleviate liver injury in mice caused by continuous high-dose-alcohol exposure by protecting the intestinal barrier, rebuilding the gut microbiota and regulating AMPK and TLR4/NF-κB signaling pathways[J]. Food Function, 2025, 16 (16): 6687- 6702. doi: 10.1039/D5FO00915D
11	Xiong SY, Wu GS, Li C, et al. Clinical efficacy of probiotics in the treatment of alcoholic liver disease: a systematic review and meta-analysis[J]. Front Cell Infect Microbiol, 2024, 14, 1358063. doi: 10.3389/fcimb.2024.1358063
12	Mao H, Zhao X, Sun S. NF-κB in inflammation and cancer [J]. Cell Mol Immunol, 2025: 1-29.
13	Qing G, Yizi J, Xinyu C, et al. NF-κB in biology and targeted therapy: new insights and translational implications[J]. Signal Trans Targeted Therapy, 2024, 9 (1): 53- 53. doi: 10.1038/s41392-024-01757-9
14	Louvet A, Mathurin P. Pathophysiology of alcoholic hepatitis[J]. Nat Rev Gastroenterol Hepatol, 2021, 18 (11): 712- 728. doi: 10.1186/s12967-023-04166-8
15	Sun L, Wen S, Li Q, et al. L-theanine relieves acute alcoholic liver injury by regulating the TNF-α/NF-κB signaling pathway in C57BL/6J mice[J]. J Fun Foods, 2021, 86, 104699. doi: 10.1016/j.jff.2021.104699
16	Wang M, Zhao L, Wang Y, et al. Sugarcane molasses polyphenol extract attenuates alcohol-induced chronic liver damage via antioxidant, anti-inflammatory, and CYP2E1/Keap1/NF-κB pathway modulation[J]. Nutrients, 2025, 17 (9): 1589. doi: 10.3390/nu17091589
17	Gerber-Tichet E, Blanchet FP, Majzoub K, et al. Toll-like receptor 4-a multifunctional virus recognition receptor[J]. Trends Microbiol, 2025, 33 (1): 34- 47. doi: 10.1016/j.tim.2024.07.001
18	Zhang Y, Dou Z, Li S, et al. An ultrasonic degraded polysaccharide extracted from Pueraria lobata ameliorate ischemic brain injury in mice by regulating the gut microbiota and LPS-TLR4 pathway[J]. Ultrasonics Sonochemistry, 2025, 112, 107200. doi: 10.1016/j.ultsonch.2024.107200
19	Ciesielska A, Matyjek M, Kwiatkowska K. TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling[J]. Cell Mol Life Sci, 2021, 78, 1233- 1261. doi: 10.1007/s00018-020-03656-y
20	谢永华, 田力, 温扬敏. 穗花杉双黄酮对酒精肝损伤小鼠TLR4/NF-κB通路和肠道细菌的影响[J]. 热带医学杂志, 2025, 25 (5): 621- 626+643+729.
21	Mou WL, Chen SR, Wu ZT, et al. LPS-TLR4/MD-2–TNF-α signaling mediates alcohol-induced liver fibrosis in rats[J]. J Toxicol Pathol, 2022, 35 (2): 193- 203. doi: 10.1293/tox.2021-0018
22	蔡世揿, 周素芳, 周丽芳, 等. 参苓白术散调控TLR4/NLRP3通路对酒精性肝病治疗作用的机制研究[J]. 中国中药杂志, 2024, 49 (5): 1275- 1285.
23	Cabral JE, Wu A, Zhou H, et al. Targeting the NLRP3 inflammasome for inflammatory disease therapy[J]. Trends Pharmacol Sci, 2025, 46 (6): 503- 519. doi: 10.1016/j.tips.2025.04.007
24	Bai T, Guo HL, Wang F, et al. Gut microbiota and HMGB1/NLRP3/GSDMD inflammasome-dependent pyroptosis: mechanisms by physcion ameliorates alcoholic liver fibrosis[J]. Front Pharmacol, 2025, 16, 1532590. doi: 10.3389/fphar.2025.1532590
25	Dong L, Zhang H, Kang Y, et al. NLRP3 and gut–liver axis: New possibility for the treatment of alcohol‐associated liver disease[J]. J Gastroenterol Hepatol, 2025, 40 (5): 1070- 1078. doi: 10.1111/jgh.16935
26	吴琰, 圣炜, 王立顺, 等. 清肝活血方调控Caspase-4/Caspase-3/GSDME介导的细胞焦亡改善酒精性肝损伤[J]. 天津中医药, 2024, 41 (6): 773- 780.
27	Wu S, Wen F, Zhong X, et al. Astragaloside IV ameliorate acute alcohol-induced liver injury in mice via modulating gut microbiota and regulating NLRP3/caspase-1 signaling pathway[J]. Ann Med, 2023, 55 (1): 2216942. doi: 10.1080/07853890.2023.2216942
28	Wang X, Liu R, Liu D. The role of the MAPK signaling pathway in cardiovascular disease: pathophysiological mechanisms and clinical therapy[J]. Int J Mol Sci, 2025, 26 (6): 2667. doi: 10.3390/ijms26062667
29	He YX, Xiong JX, Liu JM, et al. Dahuang Zhechong pill alleviates liver fibrosis progression by regulating p38 MAPK/NF-κB/TGF-β1 pathway[J]. Chin J Int Med, 2024, 30 (12): 1- 8.
30	Chen J, Ou G, Gu W, et al. Role in preventing alcoholic liver disease progression: A comparative study of whole-component finger citron essential oil and its major component d-limonene[J]. Nutrients, 2025, 17 (7): 1255. doi: 10.3390/nu17071255
31	Xiao Z, Zhicheng D, Hui F, et al. Scutellarin prevents acute alcohol-induced liver injury via inhibiting oxidative stress by regulating the Nrf2/HO-1 pathway and inhibiting inflammation by regulating the AKT, p38 MAPK/NF-κB pathways[J]. J Zhejiang University Sci B, 2023, 24 (7): 11- 15.
32	Samad MA, Ahmad I, Hasan A, et al. STAT3 signaling pathway in health and disease[J]. Med Comm, 2025, 6 (4): e70152.
33	Zhang H, Yu S, Wang Y, et al. Targeting eukaryotic elongation factor 1A: How small-molecule inhibitors suppress tumor growth via diverse pathways[J]. Int J Mol Sci, 2025, 26 (15): 7331. doi: 10.3390/ijms26157331
34	Zhai L, Du C, Zhao Q, et al. The role of IRAK-M in pulmonary diseases: Mechanisms and therapeutic implications [J]. J Inn Immu, 2025, 1-22.
35	Wan YM, Li Z, Zhou Q, et al. Mesenchymal stem cells alleviate liver injury induced by chronic-binge ethanol feeding in mice via release of TSG6 and suppression of STAT3 activation[J]. Stem Cell Res Ther, 2020, 11, 1- 13. doi: 10.1186/s13287-019-1471-y
36	Fang X, Cao J, Tao Z, et al. Hydroxytyrosol attenuates ethanol-induced liver injury by ameliorating steatosis, oxidative stress and hepatic inflammation by interfering STAT3/iNOS pathway[J]. Redox Report, 2023, 28 (1): 2187564. doi: 10.1080/13510002.2023.2187564
37	Li RN, Zheng YN, Geng HJ, et al. Role and mechanisms of the mTOR signalling pathway in the synthesis of milk components[J]. Modern Agricul, 2025, 3 (1): e70009. doi: 10.1002/moda.70009
38	Shi C, Hu S, Liu S, et al. Emerging role of exosomes during the pathogenesis of viral hepatitis, non-alcoholic steatohepatitis and alcoholic hepatitis[J]. Hum Cell, 2024, 38 (1): 26. doi: 10.1007/s13577-024-01158-8
39	杨佳, 党凯, 薛美兰, 等. 岩藻多糖对酒精暴露小鼠肝损伤的保护作用及机制[J]. 食品科学, 2023, 44 (3): 137- 145.
40	Sarode G, Hsu MF, Haj FG, et al. Interleukin-6 trans signaling regulates neutrophilic inflammation in alcohol-associated hepatitis [J]. Am J Pathol, 2025, S0002-9440(25)00209-3.
41	Efiong EE, Maedler K, Effa E, et al. Decoding diabetic kidney disease: a comprehensive review of interconnected pathways, molecular mediators, and therapeutic insights[J]. Diabetol Metab Syn, 2025, 17 (1): 192. doi: 10.1186/s13098-025-01726-4
42	卜义凡, 朴圣爱, 李紫薇, 等. 尖叶假龙胆不同组分对酒精性肝损伤模型大鼠的保护作用研究[J]. 环球中医药, 2022, 15 (8): 1329- 1336.
43	申苏建, 卢光荣, 吴利敏, 等. 参麦注射液对重症酒精性肝炎患者抗氧化作用及血清IL-6、IL-12、TNF-α水平的影响[J]. 中华中医药学刊, 2019, 37 (10): 2554- 2557.
44	Jang D, Lee AH, Shin HY, et al. The role of tumor necrosis factor alpha (TNF-α) in autoimmune disease and current TNF-α inhibitors in therapeutics[J]. Int J Mol Sci, 2021, 22 (5): 2719. doi: 10.3390/ijms22052719
45	Yang YM, Cho YE, Hwang S. Crosstalk between oxidative stress and inflammatory liver injury in the pathogenesis of alcoholic liver disease[J]. Int J Mol Sci, 2022, 23 (2): 774. doi: 10.3390/ijms23020774
46	田晓娟, 郭元虎, 李慧妍. 英夫利昔单抗治疗重症酒精性肝炎的系统评价[J]. 中国医师进修杂志, 2014 (12): 3.
47	Adekunle AD, Adejumo A, Singal AK. Therapeutic targets in alcohol-associated liver disease: progress and challenges [J]. Thera Adv Gastroenterol, 2023, 16: 17562848231170946.
48	Menon KVN, Stadheim L, Kamath PS, et al. A pilot study of the safety and tolerability of etanercept in patients with alcoholic hepatitis[J]. Off J Am Coll Gastroenterol, 2004, 99 (2): 255- 260. doi: 10.1111/j.1572-0241.2004.04034.x
49	Boetticher NC, Peine CJ, Kwo P, et al. A randomized, double-blinded, placebo-controlled multicenter trial of etanercept in the treatment of alcoholic hepatitis[J]. Gastroenterol, 2008, 135 (6): 1953- 1960. doi: 10.1053/j.gastro.2008.08.057

信号网络	有效组分/ 小分子抑制剂	不同效应及组织病理变化	作用机制	参考文献
NF-κB	PDTC （NF-κB拮抗剂）	缓解氧化应激；降低肝细胞凋亡和肝组织损伤	抑制IκBa磷酸化	[15]
NF-κB	甘蔗糖蜜多酚提取物	阻断炎症级联反应	下调TNF-α、NF-κB的表达	[16]
TLR4	穗花杉双黄酮	减轻肝脏炎症反应	抑制TLR4/NF-κB/TNF-α信号通路	[20]
	TLR4/MD-2抗体	胶原纤维沉积减少；缓解肝纤维化；减少肝细胞凋亡	抑制LPS-TLR4/MD-2-TNF-α信号通路	[21]
	参苓白术散	减少肝细胞脂滴空泡数量；炎性细胞浸润减少	下调TNF-α、TLR4表达	[22]
NLRP3	清肝活血方	降低肝脏脂质累积；减轻炎性细胞浸润	下调TNF-α、NLRP3表达	[26]
NLRP3	黄芪甲苷Ⅳ	减轻肝脏炎症反应	下调TNF-α、NLRP3表达	[27]
MAPK	佛手精油	缓解肝脏组织结构紊乱；抑制炎性细胞浸润	抑制TNF-α、MAPK表达	[30]
MAPK	SB203580 （p38 MAPK抑制剂）	减轻肝脏炎症	下调TNF-α、p38 MAPK表达	[31]
STAT3	AG490 （STAT3抑制剂）	缓解肝脏炎症反应	抑制STAT3磷酸化	[35]
STAT3	Hydroxytyrosol	减轻炎性细胞浸润	抑制STAT3/iNOS/TNF-α信号通路	[36]
mTOR	岩藻多糖	改善肝脏脂质代谢紊乱及肝脏变形	下调TNF-α、p-mTORC1和p-p70S6K表达	[39]
TGF-β1	尖叶假龙胆	降低MDA含量，加速酒精代谢	抑制TNF-α和TGF-β1表达	[42]
IL-6	参麦注射液	改善肝功能；减轻炎症反应	下调TNF-α、IL-6的表达	[43]

信号网络	有效组分/ 小分子抑制剂	不同效应及组织病理变化	作用机制	参考文献
NF-κB	PDTC （NF-κB拮抗剂）	缓解氧化应激；降低肝细胞凋亡和肝组织损伤	抑制IκBa磷酸化	[15]
NF-κB	甘蔗糖蜜多酚提取物	阻断炎症级联反应	下调TNF-α、NF-κB的表达	[16]
TLR4	穗花杉双黄酮	减轻肝脏炎症反应	抑制TLR4/NF-κB/TNF-α信号通路	[20]
	TLR4/MD-2抗体	胶原纤维沉积减少；缓解肝纤维化；减少肝细胞凋亡	抑制LPS-TLR4/MD-2-TNF-α信号通路	[21]
	参苓白术散	减少肝细胞脂滴空泡数量；炎性细胞浸润减少	下调TNF-α、TLR4表达	[22]
NLRP3	清肝活血方	降低肝脏脂质累积；减轻炎性细胞浸润	下调TNF-α、NLRP3表达	[26]
NLRP3	黄芪甲苷Ⅳ	减轻肝脏炎症反应	下调TNF-α、NLRP3表达	[27]
MAPK	佛手精油	缓解肝脏组织结构紊乱；抑制炎性细胞浸润	抑制TNF-α、MAPK表达	[30]
MAPK	SB203580 （p38 MAPK抑制剂）	减轻肝脏炎症	下调TNF-α、p38 MAPK表达	[31]
STAT3	AG490 （STAT3抑制剂）	缓解肝脏炎症反应	抑制STAT3磷酸化	[35]
STAT3	Hydroxytyrosol	减轻炎性细胞浸润	抑制STAT3/iNOS/TNF-α信号通路	[36]
mTOR	岩藻多糖	改善肝脏脂质代谢紊乱及肝脏变形	下调TNF-α、p-mTORC1和p-p70S6K表达	[39]
TGF-β1	尖叶假龙胆	降低MDA含量，加速酒精代谢	抑制TNF-α和TGF-β1表达	[42]
IL-6	参麦注射液	改善肝功能；减轻炎症反应	下调TNF-α、IL-6的表达	[43]

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