血红素氧合酶1调节铁死亡在非酒精性脂肪性肝病中的研究进展

doi:10.12114/j.issn.1007-9572.2023.0266

中国全科医学 ›› 2024, Vol. 27 ›› Issue (14): 1782-1788.DOI: 10.12114/j.issn.1007-9572.2023.0266

• 综述与专论 • 上一篇

血红素氧合酶1调节铁死亡在非酒精性脂肪性肝病中的研究进展

曹佳岑¹^,²^,³, 张宏坤¹^,²^,³, 赵文¹^,²^,³, 南月敏⁴^,^*(), 李冬冬¹^,²^,³^,^*()

1．233030　安徽省蚌埠市，蚌埠医科大学第一附属医院感染科
2．233030　安徽省蚌埠市，国家感染性疾病临床医学研究中心核心合作单位
3．233030　安徽省蚌埠市，慢性疾病免疫学基础与临床安徽省重点实验室
4．050000　河北省石家庄市，河北医科大学第三医院中西医肝病科

收稿日期:2023-04-15 修回日期:2023-07-21 出版日期:2024-05-15 发布日期:2024-03-22
通讯作者: 南月敏, 李冬冬
作者贡献：
曹佳岑负责文章的构思与设计、论文撰写；李冬冬负责论文修订、文章的质量控制，对文章整体负责，监督管理；张宏坤、赵文负责研究资料的收集与整理；南月敏负责文章指导及审校。
基金资助:
安徽省自然科学基金资助项目(2108085QH314); 安徽省卫生健康科研项目(AHWJ2022b078); 天晴肝病基金(TQGB20210163)

Progress of Heme Oxygenase-1 Mediated Ferroptosis in Non-alcoholic Fatty Liver Disease

CAO Jiacen¹^,²^,³, ZHANG Hongkun¹^,²^,³, ZHAO Wen¹^,²^,³, NAN Yuemin⁴^,^*(), LI Dongdong¹^,²^,³^,^*()

1. Department of Infection, the First Affiliated Hospital of Bengbu Medical University, Bengbu 233030, China
2. National Clinical Research Center for Infectious Diseases, Bengbu 233030, China
3. Anhui Provincial Key Laboratory of Basic and Clinical Immunology of Chronic Disease, Bengbu 233030, China
4. Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang 050000, China

Received:2023-04-15 Revised:2023-07-21 Published:2024-05-15 Online:2024-03-22
Contact: NAN Yuemin, LI Dongdong

分享到

摘要/Abstract

摘要： 铁死亡是一种新型的细胞程序性死亡方式，在非酒精性脂肪性肝病（NAFLD）进展中发挥重要作用。研究表明，作为一种诱导型氧化酶，血红素氧合酶1（HO-1）可以对抗氧化应激反应、抑制肝细胞坏死等，阻止或延缓NAFLD的进展。但HO-1如何通过调控铁死亡的发生进而影响NAFLD发生、发展的作用机制研究甚少。本文通过归纳近年来相关文献，系统、全面地总结了HO-1通过调控铁死亡的发生对NAFLD的影响，探讨了HO-1阻止NAFLD发生及进展的作用机制。本文表明，在NAFLD中，HO-1分别从合成抗氧化物（包括胆红素、一氧化碳等）、激活System Xc系统、促进亚铁离子的蓄积等方面调控铁死亡，以期为药物干预等方法靶向性HO-1基因治疗NAFLD提供理论依据，并为NAFLD的深入研究提供借鉴。

关键词: 非酒精性脂肪性肝病, 血红素氧合酶1, 铁死亡, 综述

Abstract:

Ferroptosis plays an important role in the progression of non-alcoholic fatty liver disease (NAFLD) as a novel mode of programmed cell death. Heme oxygenase-1 (HO-1), acting as an inducible oxidase, has been shown the capability of alleviating oxidative stress and hepatocyte necrosis to prevent or delay the progression of NAFLD. However, the mechanism of HO-1 regulating ferroptosis and affecting the development of NAFLD remains inadequately explored. This review provided a systematic and comprehensive summary of the effects of HO-1 on NAFLD by regulating ferroptosis, and discussed the mechanism of HO-1 in preventing the development of NAFLD by summarizing the relevant literature in recent years, and showed that HO-1 regulates ferroptosis in NAFLD through the generation of antioxidants (such as bilirubin and CO), activation of the System Xc, and facilitation of ferrous ion accumulation, in order to provide a theoretical basis for targeting HO-1 gene therapy for NAFLD by methods such as pharmacological interventions and provide a reference for further research.

Key words: Non-alcoholic fatty liver disease, Heme oxygenase-1, Ferroptosis, Review

中图分类号:

R 575.5

曹佳岑,张宏坤,赵文,等. 血红素氧合酶1调节铁死亡在非酒精性脂肪性肝病中的研究进展[J]. 中国全科医学, 2024, 27(14): 1782-1788. DOI: 10.12114/j.issn.1007-9572.2023.0266.
CAO Jiacen,ZHANG Hongkun,ZHAO Wen, et al. Progress of Heme Oxygenase-1 Mediated Ferroptosis in Non-alcoholic Fatty Liver Disease[J]. Chinese General Practice, 2024, 27(14): 1782-1788. DOI: 10.12114/j.issn.1007-9572.2023.0266.

参考文献 51

[1]	LIU J Y，TIAN Y，FU X，et al. Estimating global prevalence，incidence，and outcomes of non-alcoholic fatty liver disease from 2000 to 2021：systematic review and meta-analysis[J]. Chin Med J，2022，135（14）：1682-1691. DOI：10.1097/CM9.0000000000002277.
[2]	LI D D，YUAN X W，DONG S M，et al. Heme oxygenase-1 prevents non-alcoholic steatohepatitis through modulating mitochondrial quality control[J]. Acta Physiol，2023，237（3）：e13918. DOI：10.1111/apha.13918.
[3]	DIXON S J，PRATT D A. Ferroptosis：a flexible constellation of related biochemical mechanisms[J]. Mol Cell，2023，83（7）：1030-1042. DOI：10.1016/j.molcel.2023.03.005.
[4]	XIANG X H，GAO J B，SU D Y，et al. The advancements in targets for ferroptosis in liver diseases[J]. Front Med，2023，10：1084479. DOI：10.3389/fmed.2023.1084479.
[5]	CONSOLI V，SORRENTI V，GROSSO S，et al. Heme oxygenase-1 signaling and redox homeostasis in physiopathological conditions[J]. Biomolecules，2021，11（4）：589. DOI：10.3390/biom11040589.
[6]	STEC D E，JR HINDS T D. Natural product heme oxygenase inducers as treatment for nonalcoholic fatty liver disease[J]. Int J Mol Sci，2020，21（24）：9493. DOI：10.3390/ijms21249493.
[7]	LI D D，ZHAO D D，DU J H，et al. Heme oxygenase-1 alleviated non-alcoholic fatty liver disease via suppressing ROS-dependent endoplasmic reticulum stress[J]. Life Sci，2020，253：117678. DOI：10.1016/j.lfs.2020.117678.
[8]	李卓，陈梦璇，汪苇杭，等. Mn-SOD通过GSK-3β影响HO-1和Drp1的抗氧化应激减轻MTX相关肝细胞损伤[J]. 中南大学学报：医学版，2022，47（9）：1191-1199. DOI：10.11817/j.issn.1672-7347.2022.220305.
[9]	HAN S T，LIN F Y，QI Y C，et al. HO-1 contributes to luteolin-triggered ferroptosis in clear cell renal cell carcinoma via increasing the labile iron pool and promoting lipid peroxidation[J]. Oxid Med Cell Longev，2022，2022：3846217. DOI：10.1155/2022/3846217.
[10]	HU L，TIAN K，ZHANG T，et al. Cyanate induces oxidative stress injury and abnormal lipid metabolism in liver through Nrf2/HO-1[J]. Molecules，2019，24（18）：3231. DOI：10.3390/molecules24183231.
[11]	WEI R R，ZHAO Y Q，WANG J，et al. Tagitinin C induces ferroptosis through PERK-Nrf2-HO-1 signaling pathway in colorectal cancer cells[J]. Int J Biol Sci，2021，17（11）：2703-2717. DOI：10.7150/ijbs.59404.
[12]	PENGNET S，SUMARITHUM P，PHONGNU N，et al. Naringin attenuates fructose-induced NAFLD progression in rats through reducing endogenous triglyceride synthesis and activating the Nrf2/HO-1 pathway[J]. Front Pharmacol，2022，13：1049818. DOI：10.3389/fphar.2022.1049818.
[13]	JIN M Y，WEI Y F，YU H，et al. Erythritol improves nonalcoholic fatty liver disease by activating Nrf2 antioxidant capacity[J]. J Agric Food Chem，2021，69（44）：13080-13092. DOI：10.1021/acs.jafc.1c05213.
[14]	任柏樾，卢秉久. 泽明红山颗粒激活Nrf2/HO-1通路抑制非酒精性脂肪性肝炎小鼠肝损伤[J]. 解剖科学进展，2021，27（3）：350-353，357. DOI：10.16695/j.cnki.1006-2947.2021.03.024.
[15]	LI S W，TAKAHARA T，QUE W T，et al. Hydrogen-rich water protects against liver injury in nonalcoholic steatohepatitis through HO-1 enhancement via IL-10 and Sirt 1 signaling[J]. Am J Physiol Gastrointest Liver Physiol，2021，320（4）：G450-463. DOI：10.1152/ajpgi.00158.2020.
[16]	XU Q S，FAN Y H，LOOR J J，et al. Aloin protects mice from diet-induced non-alcoholic steatohepatitis via activation of Nrf2/HO-1 signaling[J]. Food Funct，2021，12（2）：696-705. DOI：10.1039/d0fo02684k.
[17]	NAN Y M，WANG R Q，ZHAO S X，et al. Heme oxygenase-1 prevents non-alcoholic steatohepatitis through suppressing hepatocyte apoptosis in mice[J]. Lipids Health Dis，2010，9：124. DOI：10.1186/1476-511X-9-124.
[18]	RYTER S W. Therapeutic potential of heme oxygenase-1 and carbon monoxide in acute organ injury，critical illness，and inflammatory disorders[J]. Antioxidants，2020，9（11）：1153. DOI：10.3390/antiox9111153.
[19]	CAI X P，HUA S Y，DENG J W，et al. Astaxanthin activated the Nrf2/HO-1 pathway to enhance autophagy and inhibit ferroptosis，ameliorating acetaminophen-induced liver injury[J]. ACS Appl Mater Interfaces，2022，14（38）：42887-42903. DOI：10.1021/acsami.2c10506.
[20]	HU J J，ZHU Z J，YING H L，et al. Oleoylethanolamide protects against acute liver injury by regulating Nrf-2/HO-1 and NLRP3 pathways in mice[J]. Front Pharmacol，2020，11：605065. DOI：10.3389/fphar.2020.605065.
[21]	邓玉娇. 罗格列酮抑制ACSL4介导的脂质过氧化通路调控HUVEC铁死亡[D]. 天津：天津医科大学，2020.
[22]	JIANG X J，STOCKWELL B R，CONRAD M. Ferroptosis：mechanisms，biology and role in disease[J]. Nat Rev Mol Cell Biol，2021，22（4）：266-282. DOI：10.1038/s41580-020-00324-8.
[23]	URSINI F，MAIORINO M. Lipid peroxidation and ferroptosis：the role of GSH and GPx4[J]. Free Radic Biol Med，2020，152：175-185. DOI：10.1016/j.freeradbiomed.2020.02.027.
[24]	LIU B，YI W，MAO X X，et al. Enoyl coenzyme A hydratase 1 alleviates nonalcoholic steatohepatitis in mice by suppressing hepatic ferroptosis[J]. Am J Physiol Endocrinol Metab，2021，320（5）：E925-937. DOI：10.1152/ajpendo.00614.2020.
[25]	TSURUSAKI S，TSUCHIYA Y，KOUMURA T，et al. Hepatic ferroptosis plays an important role as the trigger for initiating inflammation in nonalcoholic steatohepatitis[J]. Cell Death Dis，2019，10（6）：449. DOI：10.1038/s41419-019-1678-y.
[26]	LIU Y，WAN Y C，JIANG Y，et al. GPX4：the hub of lipid oxidation，ferroptosis，disease and treatment[J]. Biochim Biophys Acta Rev Cancer，2023，1878（3）：188890. DOI：10.1016/j.bbcan.2023.188890.
[27]	WU J，WANG Y，JIANG R T，et al. Ferroptosis in liver disease：new insights into disease mechanisms[J]. Cell Death Discov，2021，7（1）：276. DOI：10.1038/s41420-021-00660-4.
[28]	TONG J，LI D J，MENG H B，et al. Targeting a novel inducible GPX4 alternative isoform to alleviate ferroptosis and treat metabolic-associated fatty liver disease[J]. Acta Pharm Sin B，2022，12（9）：3650-3666. DOI：10.1016/j.apsb.2022.02.003.
[29]	CHEN J Y，LI X P，GE C D，et al. The multifaceted role of ferroptosis in liver disease[J]. Cell Death Differ，2022，29（3）：467-480. DOI：10.1038/s41418-022-00941-0.
[30]	LI J，CAO F，YIN H L，et al. Ferroptosis：past，present and future[J]. Cell Death Dis，2020，11（2）：88. DOI：10.1038/s41419-020-2298-2.
[31]	LI X Y，WANG T X，HUANG X M，et al. Targeting ferroptosis alleviates methionine-choline deficient （MCD）-diet induced NASH by suppressing liver lipotoxicity[J]. Liver Int，2020，40（6）：1378-1394. DOI：10.1111/liv.14428.
[32]	ZHU Z X，ZHANG Y，HUANG X H，et al. Thymosin beta 4 alleviates non-alcoholic fatty liver by inhibiting ferroptosis via up-regulation of GPX4[J]. Eur J Pharmacol，2021，908：174351. DOI：10.1016/j.ejphar.2021.174351.
[33]	张闪闪. 高脂性肥胖诱导的肝脏铁缺乏对胰岛素抵抗的影响及机制研究[D]. 武汉：华中科技大学，2017.
[34]	MOU Y H，WANG J，WU J C，et al. Ferroptosis，a new form of cell death：opportunities and challenges in cancer[J]. J Hematol Oncol，2019，12（1）：34. DOI：10.1186/s13045-019-0720-y.
[35]	CAPELLETTI M M，MANCEAU H，PUY H，et al. Ferroptosis in liver diseases：an overview[J]. Int J Mol Sci，2020，21（14）：4908. DOI：10.3390/ijms21144908.
[36]	GAO G，XIE Z S，LI E W，et al. Dehydroabietic acid improves nonalcoholic fatty liver disease through activating the Keap1/Nrf2-ARE signaling pathway to reduce ferroptosis[J]. J Nat Med，2021，75（3）：540-552. DOI：10.1007/s11418-021-01491-4.
[37]	KWON M Y，PARK E，LEE S J，et al. Heme oxygenase-1 accelerates erastin-induced ferroptotic cell death[J]. Oncotarget，2015，6（27）：24393-24403. DOI：10.18632/oncotarget.5162.
[38]	LIAO S J，HUANG M，LIAO Y L，et al. HMOX1 promotes ferroptosis induced by erastin in lens epithelial cell through modulates Fe²⁺ production[J]. Curr Eye Res，2023，48（1）：25-33. DOI：10.1080/02713683.2022.2138450.
[39]	ZHANG Z L，GUO M，SHEN M，et al. The BRD7-P53-SLC25A28 axis regulates ferroptosis in hepatic stellate cells[J]. Redox Biol，2020，36：101619. DOI：10.1016/j.redox.2020.101619.
[40]	SHEN X H，HU B，XU G T，et al. Activation of Nrf2/HO-1 pathway by glycogen synthase kinase-3β inhibition attenuates renal ischemia/reperfusion injury in diabetic rats[J]. Kidney Blood Press Res，2017，42（2）：369-378. DOI：10.1159/000477947.
[41]	LI J C，LU K M，SUN F L，et al. Panaxydol attenuates ferroptosis against LPS-induced acute lung injury in mice by Keap1-Nrf2/HO-1 pathway[J]. J Transl Med，2021，19（1）：96. DOI：10.1186/s12967-021-02745-1.
[42]	KERINS M J，OOI A. The roles of NRF2 in modulating cellular iron homeostasis[J]. Antioxid Redox Signal，2018，29（17）：1756-1773. DOI：10.1089/ars.2017.7176.
[43]	LIN C H，LIN P P，LIN C Y，et al. Decreased mRNA expression for the two subunits of system xc （-），SLC3A2 and SLC7A11，in WBC in patients with schizophrenia：evidence in support of the hypo-glutamatergic hypothesis of schizophrenia[J]. J Psychiatr Res，2016，72：58-63. DOI：10.1016/j.jpsychires.2015.10.007.
[44]	YAO X X，YANG P，JIN Z K，et al. Multifunctional nanoplatform for photoacoustic imaging-guided combined therapy enhanced by CO induced ferroptosis[J]. Biomaterials，2019，197：268-283. DOI：10.1016/j.biomaterials.2019.01.026.
[45]	HUANG Y，YE Z，MA T J，et al. Carbon monoxide （CO） modulates hydrogen peroxide （H₂O₂）-mediated cellular dysfunction by targeting mitochondria in rabbit lens epithelial cells[J]. Exp Eye Res，2018，169：68-78. DOI：10.1016/j.exer.2018.01.023.
[46]	DONG H，QIANG Z Z，CHAI D D，et al. Nrf2 inhibits ferroptosis and protects against acute lung injury due to intestinal ischemia reperfusion via regulating SLC7A11 and HO-1[J]. Aging，2020，12（13）：12943-12959. DOI：10.18632/aging.103378.
[47]	TANG Z M，JU Y H，DAI X C，et al. HO-1-mediated ferroptosis as a target for protection against retinal pigment epithelium degeneration[J]. Redox Biol，2021，43：101971. DOI：10.1016/j.redox.2021.101971.
[48]	BALLA G，JACOB H S，BALLA J，et al. Ferritin：a cytoprotective antioxidant strategem of endothelium[J]. J Biol Chem，1992，267（25）：18148-18153.
[49]	SOARES M P，SELDON M P，GREGOIRE I P，et al. Heme oxygenase-1 modulates the expression of adhesion molecules associated with endothelial cell activation[J]. J Immunol，2004，172（6）：3553-3563. DOI：10.4049/jimmunol.172.6.3553.
[50]	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.
[51]	CHEN Z，TIAN R F，SHE Z G，et al. Role of oxidative stress in the pathogenesis of nonalcoholic fatty liver disease[J]. Free Radic Biol Med，2020，152：116-141. DOI：10.1016/j.freeradbiomed.2020.02.025.

血红素氧合酶1调节铁死亡在非酒精性脂肪性肝病中的研究进展

Progress of Heme Oxygenase-1 Mediated Ferroptosis in Non-alcoholic Fatty Liver Disease

RichHTML

PDF

可视化

摘要/Abstract

引用本文

使用本文

参考文献 51

相关文章 15

编辑推荐

Metrics

留言

[1]	倪嘉淳, 蔡增进, 侯长城, 江琼, 康健, 杨向东, 樊文彬. 痔病评估分类法研究进展及评估价值分析[J]. 中国全科医学, 2024, 27(20): 2545-2550.
[2]	侯娜娜, 冯金章, 刘锁红, 冯俊芳, 薛小艳, 尹娜, 迟戈夫. 血尿酸/肌酐比值与代谢相关脂肪性肝病的相关性研究[J]. 中国全科医学, 2024, 27(20): 2476-2482.
[3]	李孟野, 姜一农. 可溶性肾素前体受体在多系统疾病中的研究进展[J]. 中国全科医学, 2024, 27(18): 2295-2300.
[4]	康殷楠, 石嘉琪, 王俊科, 李斌, 李初谊, 马俊, 于晓辉. 抗体药物偶联物在人表皮生长因子受体2低表达胃癌中的应用研究进展[J]. 中国全科医学, 2024, 27(18): 2287-2294.
[5]	胥梓薇, 程康耀, 桂莉. 突发重大传染病事件背景下过负荷医院管理研究的范围综述[J]. 中国全科医学, 2024, 27(16): 2039-2044.
[6]	倪雪桐, 王若羲, 张晶, 杨兴华. 非酒精性脂肪性肝病、代谢相关脂肪性肝病与心血管疾病关联的国内外研究进展[J]. 中国全科医学, 2024, 27(16): 2033-2038.
[7]	吴美倩, 肖进, 李斐斐, 胡镕镕, 刘彩霞. 24小时活动行为：老年人健康影响因素研究的新方向[J]. 中国全科医学, 2024, 27(15): 1911-1916.
[8]	王芳芳, 朱莉, 幸佳佳, 庞日朝, 苟翔, 张安仁. 创伤性中枢神经系统损伤后肠道屏障变化及其可能机制的研究进展[J]. 中国全科医学, 2024, 27(14): 1775-1781.
[9]	杜书琴, 钱立锋, 熊烈, 史汉强, 石彦波. 铁死亡：抑郁症治疗的新靶点[J]. 中国全科医学, 2024, 27(12): 1417-1423.
[10]	冉东升, 逯艳艳, 辛春玲, 马颖才. 血脂异常与结直肠锯齿状病变、结直肠癌相关性研究进展[J]. 中国全科医学, 2024, 27(12): 1424-1430.
[11]	张娜文, 黄少敏, 田利民. 成人血清骨钙素水平与非酒精性脂肪性肝病发生风险的Meta分析[J]. 中国全科医学, 2024, 27(12): 1519-1524.
[12]	杨怡然, 王纯, 邓桑杨, 江晨, 吴海鹰, 钱传云. 铁死亡在创伤性中枢神经系统损伤治疗中的研究进展[J]. 中国全科医学, 2024, 27(11): 1395-1399.
[13]	赵静静, 张志红, 甄俊平. 异柠檬酸脱氢酶基因突变在软骨肉瘤中的研究进展及展望[J]. 中国全科医学, 2024, 27(11): 1400-1404.
[14]	钟锦佳, 李文涛, 黄亚芳, 吴浩. 初级保健领域基于机器学习预测模型研究的设计特征与方法学质量：范围综述[J]. 中国全科医学, 2024, 27(10): 1271-1276.
[15]	王清玉, 林征, 雷阳, 孙彩云, 王咪, 顾珺怡, 朱展慧, 唐李晨. 儿童青少年回避性/限制性摄食障碍：评估与治疗[J]. 中国全科医学, 2024, 27(09): 1028-1033.