能量代谢在肝缺血再灌注损伤中的作用机制及靶向治疗

杨天天; 黄璐; 张校; 任亚丽; 徐维田; 张松

doi:10.12449/JCH250937

能量代谢在肝缺血再灌注损伤中的作用机制及靶向治疗

DOI: 10.12449/JCH250937

杨天天^{1, 2},
黄璐^{1, 2},
张校^{1, 2},
任亚丽^{1, 2},
徐维田²,
张松^2, , ,

1.
武汉科技大学医学部医学院，武汉 430065
2.
中国人民解放军中部战区总医院消化内科，武汉 430012

基金项目:

国家自然科学基金 (82200708);

湖北省自然科学基金 (2021CFB001)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：杨天天负责查阅文献，论文撰写与修改；黄璐负责归纳文献与资料分析；张校、任亚丽参与修改论文；徐维田负责提供指导性意见；张松负责指导论文撰写并最后定稿。

详细信息

通信作者:
张松， hbzhangs@163.com （ORCID： 0000-0002-3855-2113）

计量
- 文章访问数: 180
- HTML全文浏览量: 77
- PDF下载量: 12
- 被引次数: 0
出版历程
- 收稿日期: 2025-02-17
- 录用日期: 2025-04-11
- 出版日期: 2025-09-25

Mechanism of action of energy metabolism in hepatic ischemia-reperfusion injury and related targeted therapies

Tiantian YANG^{1, 2},
Lu HUANG^{1, 2},
Xiao ZHANG^{1, 2},
Yali REN^{1, 2},
Weitian XU²,
Song ZHANG^{2
, ,
,}

1.
School of Medicine，Wuhan University of Science and Technology，Wuhan 430065，China
2.
Department of Gastroenterology，General Hospital of Central Theater Command，Wuhan 430012，China

Research funding:

National Natural Science Foundation of China (82200708);

Natural Science Foundation of Hubei Province (2021CFB001)

More Information

Corresponding author: ZHANG Song， hbzhangs@163.com （ORCID： 0000-0002-3855-2113）

摘要

摘要: 肝缺血再灌注损伤（HIRI）是肝移植、肝部分切除术等手术过程中不可避免的主要并发症，其防治也是临床上的热点与难点问题。本文重点综述肝缺血再灌注过程中由能量代谢障碍引发损伤的机制及治疗策略，并总结当前与代谢相关的治疗进展，旨在为进一步阐明HIRI的发生机制、探索临床有效的HIRI防治策略提供新的思路。
- 再灌注损伤 /
- 能量代谢 /
- 肝疾病
Abstract: Hepatic ischemia-reperfusion injury （HIRI） is an inevitable major complication during surgical procedures such as liver transplantation and partial hepatectomy， and its prevention and treatment are hotspots and difficulties in clinical practice. This article reviews the mechanism of injury caused by energy metabolism disorders during liver ischemia-reperfusion and related treatment strategies and summarizes the current advances in metabolism-related therapies， in order to provide new ideas for further clarifying the onset mechanism of HIRI and exploring effective clinical prevention and treatment strategies for HIRI.
- Reperfusion Injury /
- Energy Metabolism /
- Liver Diseases

HTML全文

注： ALOX12，花生四烯酸12-脂氧合酶；12-HETE，12-羟基二碳四烯酸；GPR31，G蛋白偶联受体31；HIF-1α/HIF-2α，缺氧诱导因子1α/2α；PGC-1α，过氧化物酶体增殖物激活受体γ共激活因子1α；CPT-1，肉碱棕榈酰转移酶1；CPT-2，肉碱棕榈酰转移酶2；ROS，活性氧；M1/M2，M1/M2型巨噬细胞。

图 1 肝脏I/R过程中能量代谢的变化

Figure 1. Changes in energy metabolism during I/R in the hepatic

下载: 全尺寸图片幻灯片

参考文献(45)

[1]	HUH J, CHAE MS. Impact of paired remote ischemic preconditioning on postreperfusion syndrome in living-donor liver transplantation: A propensity-score matching analysis[J]. Medicina(Kaunas), 2024, 60( 11): 1830. DOI: 10.3390/medicina60111830.
[2]	DENG YZ, NI LH, ZHOU ZY, et al. Research progress on the mechanism and prevention strategies of hepatic ischemia-reperfusion injury[J]. Chin J Microcirc, 2023, 33( 2): 109- 115. DOI: 10.3969/j.issn.1005-1740.2023.02.020. 邓银芝, 倪利华, 周中银, 等. 肝脏缺血再灌注损伤的机制及防治策略的研究进展[J]. 微循环学杂志, 2023, 33( 2): 109- 115. DOI: 10.3969/j.issn.1005-1740.2023.02.020.
[3]	GEORGE J, LU YK, TSUCHISHIMA M, et al. Cellular and molecular mechanisms of hepatic ischemia-reperfusion injury: The role of oxidative stress and therapeutic approaches[J]. Redox Biol, 2024, 75: 103258. DOI: 10.1016/j.redox.2024.103258.
[4]	MACHADO IF, PALMEIRA CM, ROLO AP. Preservation of mitochondrial health in liver ischemia/reperfusion injury[J]. Biomedicines, 2023, 11( 3): 948. DOI: 10.3390/biomedicines11030948.
[5]	WANG H, XI ZF, DENG L, et al. Macrophage polarization and liver ischemia-reperfusion injury[J]. Int J Med Sci, 2021, 18( 5): 1104- 1113. DOI: 10.7150/ijms.52691.
[6]	MA YN, YAO XT, ZOU YD, et al. Ticlopidine protects hepatic ischemia-reperfusion injury via suppressing ferroptosis[J]. Biochem Biophys Res Commun, 2024, 733: 150436. DOI: 10.1016/j.bbrc.2024.150436.
[7]	GAO FQ, QIU X, WANG K, et al. Targeting the hepatic microenvironment to improve ischemia/reperfusion injury: New insights into the immune and metabolic compartments[J]. Aging Dis, 2022, 13( 4): 1196- 1214. DOI: 10.14336/AD.2022.0109.
[8]	SOLIMAN E, ELSHAZLY SM, SHEWAIKH SM, et al. Reno-and hepato-protective effect of allopurinol after renal ischemia/reperfusion injury: Crosstalk between xanthine oxidase and peroxisome proliferator-activated receptor gamma signaling[J]. Food Chem Toxicol, 2023, 178: 113868. DOI: 10.1016/j.fct.2023.113868.
[9]	TEIXEIRA DA SILVA R, MACHADO IF, TEODORO JS, et al. PEG35 as a preconditioning agent against hypoxia/reoxygenation injury[J]. Int J Mol Sci, 2022, 23( 3): 1156. DOI: 10.3390/ijms23031156.
[10]	DING W, DUAN YF, QU Z, et al. Acidic microenvironment aggravates the severity of hepatic ischemia/reperfusion injury by modulating M1-polarization through regulating PPAR-γ signal[J]. Front Immunol, 2021, 12: 697362. DOI: 10.3389/fimmu.2021.697362.
[11]	GAN XJ, ZHANG RS, GU J, et al. Acidic microenvironment regulates the severity of hepatic ischemia/reperfusion injury by modulating the generation and function of tregs via the PI3K-mTOR pathway[J]. Front Immunol, 2020, 10: 2945. DOI: 10.3389/fimmu.2019.02945.
[12]	ZHOU YJ, QIU T, WANG TY, et al. Research progress on the role of mitochondria in the process of hepatic ischemia-reperfusion injury[J]. Gastroenterol Rep(Oxf), 2024, 12: goae066. DOI: 10.1093/gastro/goae066.
[13]	RENZENG ZG, YANG KJ, LU YL, et al. Research advances in neutrophil extracellular traps and liver diseases[J]. J Clin Hepatol, 2024, 40( 3): 639- 643. DOI: 10.12449/JCH240334. 仁增卓嘎, 杨康洁, 芦永良, 等. 中性粒细胞胞外诱捕网(NET)与肝脏疾病的关系[J]. 临床肝胆病杂志, 2024, 40( 3): 639- 643. DOI: 10.12449/JCH240334.
[14]	ZHANG HW, NI M, WANG H, et al. Gsk3β regulates the resolution of liver ischemia/reperfusion injury via MerTK[J]. JCI Insight, 2023, 8( 1): e151819. DOI: 10.1172/jci.insight.151819.
[15]	ZHANG XJ, CHENG X, YAN ZZ, et al. An ALOX12-12-HETE-GPR31 signaling axis is a key mediator of hepatic ischemia-reperfusion injury[J]. Nat Med, 2018, 24( 1): 73- 83. DOI: 10.1038/nm.4451.
[16]	YU S, WANG K, LI QP, et al. Nonalcoholic steatohepatitis critically rewires the ischemia/reperfusion-induced dysregulation of cardiolipins and sphingolipids in mice[J]. Hepatobiliary Surg Nutr, 2023, 12( 1): 3- 19. DOI: 10.21037/hbsn-21-133.
[17]	LI ZH, YIN B, XU YN, et al. Von Hippel-Lindau deficiency protects the liver against ischemia/reperfusion injury through the regulation of hypoxia-inducible factor 1α and 2α[J]. Hepatol Commun, 2024, 8( 12): e0567. DOI: 10.1097/HC9.0000000000000567.
[18]	LISS KHH, MOUSA M, BUCHA S, et al. Dynamic changes in the mouse hepatic lipidome following warm ischemia reperfusion injury[J]. Sci Rep, 2024, 14( 1): 3584. DOI: 10.1038/s41598-024-54122-9.
[19]	WANG SS, WANG YR, LIU R, et al. Mechanism of action and potential therapeutic targets of ferroptosis suppressor protein 1 in liver diseases[J]. J Clin Hepatol, 2024, 40( 7): 1493- 1497. DOI: 10.12449/JCH240731. 王思思, 王亚茹, 刘睿, 等. 铁死亡抑制蛋白1在肝脏疾病中的作用机制及潜在治疗靶点[J]. 临床肝胆病杂志, 2024, 40( 7): 1493- 1497. DOI: 10.12449/JCH240731.
[20]	YUAN JS, YANG MY, WU ZR, et al. The lactate-primed KAT8-PCK2 axis exacerbates hepatic ferroptosis during ischemia/reperfusion injury by reprogramming OXSM-dependent mitochondrial fatty acid synthesis[J]. Adv Sci(Weinh), 2025, 12( 11): e2414141. DOI: 10.1002/advs.202414141.
[21]	RONG J, ZHANG ZX, PENG XY, et al. Mechanisms of hepatic and renal injury in lipid metabolism disorders in metabolic syndrome[J]. Int J Biol Sci, 2024, 20( 12): 4783- 4798. DOI: 10.7150/ijbs.100394.
[22]	ZHU L, ZHOU H, XU F, et al. Hepatic ischemia-reperfusion impairs blood-brain barrier partly due to release of arginase from injured liver[J]. Front Pharmacol, 2021, 12: 724471. DOI: 10.3389/fphar.2021.724471.
[23]	KUBOTA R, HAYASHI N, KINOSHITA K, et al. Inhibition of γ-glutamyltransferase ameliorates ischaemia-reoxygenation tissue damage in rats with hepatic steatosis[J]. Br J Pharmacol, 2020, 177( 22): 5195- 5207. DOI: 10.1111/bph.15258.
[24]	XU BW, ZHANG P, TANG XL, et al. Metabolic rewiring of kynurenine pathway during hepatic ischemia-reperfusion injury exacerbates liver damage by impairing NAD homeostasis[J]. Adv Sci(Weinh), 2022, 9( 35): e2204697. DOI: 10.1002/advs.202204697.
[25]	LU TF, LI Q, LIN WW, et al. Gut microbiota-derived glutamine attenuates liver ischemia/reperfusion injury via macrophage metabolic reprogramming[J]. Cell Mol Gastroenterol Hepatol, 2023, 15( 5): 1255- 1275. DOI: 10.1016/j.jcmgh.2023.01.004.
[26]	LIU JH, ZHANG W, WANG X, et al. Unveiling the crucial roles of O 2- and ATP in hepatic ischemia-reperfusion injury using dual-color/reversible fluorescence imaging[J]. J Am Chem Soc, 2023, 145( 36): 19662- 19675. DOI: 10.1021/jacs.3c04303.
[27]	HUANG KP, WANG CY, MEI BS, et al. Bile acids attenuate hepatic inflammation during ischemia/reperfusion injury[J]. JHEP Rep, 2024, 6( 8): 101101. DOI: 10.1016/j.jhepr.2024.101101.
[28]	LI XF, WU YK, ZHANG WF, et al. Pre-conditioning with tanshinone IIA attenuates the ischemia/reperfusion injury caused by liver grafts via regulation of HMGB1 in rat Kupffer cells[J]. Biomed Pharmacother, 2017, 89: 1392- 1400. DOI: 10.1016/j.biopha.2017.03.022.
[29]	JIANG XJ, KUANG G, GONG X, et al. Glycyrrhetinic acid pretreatment attenuates liver ischemia/reperfusion injury via inhibiting TLR4 signaling cascade in mice[J]. Int Immunopharmacol, 2019, 76: 105870. DOI: 10.1016/j.intimp.2019.105870.
[30]	ZHANG N, HAN L, XUE YR, et al. The protective effect of magnesium lithospermate B on hepatic ischemia/reperfusion via inhibiting the Jak2/Stat3 signaling pathway[J]. Front Pharmacol, 2019, 10: 620. DOI: 10.3389/fphar.2019.00620.
[31]	LUO RY, ZHANG YH, WANG H, et al. Radix Rehmanniae Praeparata extracts ameliorate hepatic ischemia-reperfusion injury by restoring lipid metabolism in hepatocytes[J]. J Ethnopharmacol, 2024, 335: 118702. DOI: 10.1016/j.jep.2024.118702.
[32]	JIANG Y, HE XX, SIMONARO CM, et al. Acid ceramidase protects against hepatic ischemia/reperfusion injury by modulating sphingolipid metabolism and reducing inflammation and oxidative stress[J]. Front Cell Dev Biol, 2021, 9: 633657. DOI: 10.3389/fcell.2021.633657.
[33]	YANG XY, CHEN H, SHEN W, et al. FGF21 modulates immunometabolic homeostasis via the ALOX15/15-HETE axis in early liver graft injury[J]. Nat Commun, 2024, 15( 1): 8578. DOI: 10.1038/s41467-024-52379-2.
[34]	ZHANG LY, GONG XX, TAN J, et al. Lactobacillus reuteri mitigates hepatic ischemia/reperfusion injury by modulating gut microbiota and metabolism through the Nrf2/HO-1 signaling[J]. Biol Direct, 2024, 19( 1): 23. DOI: 10.1186/s13062-024-00462-5.
[35]	GU J, ZHANG T, GUO JR, et al. Ursodeoxycholyl lysophosphatidylethanolamide protects against hepatic ischemia/reperfusion injury via phospholipid metabolism-mediated mitochondrial quality control[J]. FASEB J, 2020, 34( 5): 6198- 6214. DOI: 10.1096/fj.201902013RRR.
[36]	JIN GH, GUO N, LIU YS, et al. 5-aminolevulinate and CHIL3/CHI3L1 treatment amid ischemia aids liver metabolism and reduces ischemia-reperfusion injury[J]. Theranostics, 2023, 13( 14): 4802- 4820. DOI: 10.7150/thno.83163.
[37]	WU YC, LI CB, KHAN AA, et al. Insulin-induced gene 2 protects against hepatic ischemia-reperfusion injury via metabolic remodeling[J]. J Transl Med, 2023, 21( 1): 739. DOI: 10.1186/s12967-023-04564-y.
[38]	DU SY, ZHANG XJ, JIA YX, et al. Hepatocyte HSPA12A inhibits macrophage chemotaxis and activation to attenuate liver ischemia/reperfusion injury via suppressing glycolysis-mediated HMGB1 lactylation and secretion of hepatocytes[J]. Theranostics, 2023, 13( 11): 3856- 3871. DOI: 10.7150/thno.82607.
[39]	ZHOU X, LI JB, WANG J, et al. Lin28 promoting the protective effect of PMSCs on hepatic ischaemia-reperfusion injury by regulating glucose metabolism[J]. J Cell Mol Med, 2023, 27( 10): 1384- 1397. DOI: 10.1111/jcmm.17739.
[40]	JAKUBAUSKIENE L, JAKUBAUSKAS M, STIEGLER P, et al. Ischemic preconditioning for liver transplantation: A systematic review and meta-analysis of randomized controlled trials[J]. Visc Med, 2021, 37( 5): 329- 337. DOI: 10.1159/000516608.
[41]	JIANG T, ZHAN F, RAO ZQ, et al. Combined ischemic and rapamycin preconditioning alleviated liver ischemia and reperfusion injury by restoring autophagy in aged mice[J]. Int Immunopharmacol, 2019, 74: 105711. DOI: 10.1016/j.intimp.2019.105711.
[42]	JIANG Y, FENG X, LIU W, et al. Annual review of global liver transplantation research in 2024:technological breakthroughs,precision management and future challenges[J]. Ogran Transplant, 2025, 16( 3): 350- 358. DOI: 10.12464/j.issn.1674-7445.2025099. 蒋勇, 冯啸, 刘炜, 等. 2024年全球肝移植研究年度盘点——技术突破、精准管理与未来挑战[J]. 器官移植, 2025, 16( 3): 350- 358. DOI: 10.12464/j.issn.1674-7445.2025099.
[43]	XIE Y, JIANG WT. Liver graft preservation and functional maintenance accelerate the development of liver transplantation[J]. Ogran Transplant, 2023, 14( 2): 201- 206. DOI: 10.3969/j.issn.1674-7445.2023.02.004. 谢炎, 蒋文涛. 供肝保存与功能维护助力肝移植发展[J]. 器官移植, 2023, 14( 2): 201- 206. DOI: 10.3969/j.issn.1674-7445.2023.02.004.
[44]	LIANG AJ, CHENG WY, CAO PH, et al. Effects of machine perfusion strategies on different donor types in liver transplantation: A systematic review and meta-analysis[J]. Int J Surg, 2023, 109( 11): 3617- 3630. DOI: 10.1097/JS9.0000000000000661.
[45]	Brand of Organ Transplant of Chinese Medical Association. Guideline on the clinical application of ex situ liver machine perfusion Branch of Organ[J/CD]. Chin J Transplant(Electronic Edition), 2024, 18( 6): 334- 345. DOI: 10.3877/cma.j.issn.1674-3903.2024.06.002. 中华医学会器官移植学分会. 肝脏体外机械灌注临床应用指南[J/CD]. 中华移植杂志(电子版), 2024, 18( 6): 334- 345. DOI: 10.3877/cma.j.issn.1674-3903.2024.06.002.