Research advances in mechanisms of ferroptosis in air pollution-related diseases
-
摘要:
流行病学研究证实，大气污染物暴露会导致人体不良健康结局，但具体的生物学机制尚不明确。空气污染暴露后，氧化应激已被证实是影响健康的经典调控机制。近年来研究发现，氧化应激导致的脂质过氧化与铁累积共同作用，可诱导调节性细胞死亡，被称为“铁死亡”。因此，铁死亡可能是空气污染物引发不良健康结局的重要机制。为了探究空气污染引发不良健康结局的铁死亡机制，基于已有研究成果，梳理了铁死亡在空气污染导致不良健康结局中的作用靶点，详细探讨了空气污染物诱导铁死亡的调控机制。系统综述结果表明：细颗粒物（PM2.5）、臭氧(ozone，O3)、香烟烟雾（cigarette smoke，CS）均可通过影响铁代谢和脂质过氧化途径中的关键基因诱发铁死亡；大气污染物对铁死亡的调控过程主要是通过引发氧化应激降低机体抗氧化能力，从而降低铁死亡的抗性。本综述结果进一步补充了空气污染诱导疾病的发生机制，可为潜在的疾病治疗策略提供理论支持。
Abstract:Epidemiologic studies have confirmed that air pollutants exposure could result in various adverse health outcomes, but the specific biological mechanism is still unclear. Oxidative stress (OS) induced by air pollution exposure has been confirmed as a classical regulatory mechanism that affects our health. In recent years, it has been found that the combined effect of lipid peroxidation induced by OS and iron accumulation can induce programmed cell death, which has been termed "ferroptosis". Thus, ferroptosis could be an important regulatory mechanism of adverse health outcomes induced by air pollutants exposure. To explore the mechanisms by which air pollution triggers ferroptosis, we reviewed and summarized the targets and regulatory mechanisms of ferroptosis in regulating adverse health outcomes caused by air pollution, based on existing research results. The result showed that fine particulate matter (PM2.5), ozone (O3) and cigarette smoke (CS) could induce ferroptosis by affecting key genes in iron metabolism and lipid peroxidation pathways. In a word, air pollutants could cause OS and reduce the antioxidant capacity, then reduce the resistance of ferroptosis. This review further supplemented the mechanism of air pollution-induced diseases, which could provide theoretical support for potential disease treatment strategies.
-
Key words:
- air pollution /
- ferroptosis /
- health effects /
- regulatory mechanisms
-
图 1 铁死亡的调控机制示意
TFRC—转铁蛋白；LOX—脂氧合酶；POR—细胞色素P450还原酶；ACSL4—酰基辅酶A合成酶长链家族成员4；LPCAT3—溶血磷脂酰基转移酶3；Cys2—胱氨酸；Cys—半胱氨酸；GCL—谷氨酸-半胱氨酸连接酶；GSS—谷胱甘肽合酶；GSH—还原型谷胱甘肽；GSSG—氧化型谷胱甘肽；GPX4—谷胱甘肽过氧化物酶4。
Figure 1. Mechanisms of ferroptosis regulation
表 1 铁死亡在不同空气污染物诱导不良健康结局中的研究进展
Table 1. Progress of ferroptosis in the induction of adverse health outcomes by different air pollutants
污染物 不良结局 作用机制 信号通路 细颗粒物（PM2.5） 呼吸系统疾病 通过诱导细胞和线粒体ROS的产生，导致氧化应激失衡，引起一系列铁死亡过程[38-45]，并且可以激活FSP1、Nrf2[46]、PI3K/Akt通路[47] xCT/SLC7A11，GPX4，FTH1，FTL，TfR1，
FSP1，PI3K/Akt/Nrf2，HO-1心血管系统疾病 铁死亡在PM2.5诱导心肌细胞损伤的机制中起着重要作用[48-49] xCT/SLC7A11，GPX4，TfR1，FTL，FTH1，
YY1，NCOA4神经系统疾病 暴露于PM2.5可能改变癫痫发作患者铁死亡相关的基因表达，并加重癫痫发作诱发的认知缺陷[50-51]，且对视神经造成损害[52] GPX4，FTH1，NF-κB/Nrf2 生殖系统疾病 PM2.5对幼年雄性大鼠精子生成功能产生影响，其中线粒体功能障碍和铁死亡是重要机制[53-54] GPX4，SLC7A11，FPN1，DMT1，
Keap1，Acsl4，Aloxe3消化系统疾病 暴露于PM2.5会增加Nrf2和HO-1的水平，并且使得Keap1下调，产生ROS诱导小肠上皮细胞铁死亡[55] Nrf2，HO-1，Keap1，
GPX4，xCT臭氧（O3） 心血管系统疾病 臭氧预处理增强了Nrf2的核易位，抑制了铁死亡，通过Nrf2/SLC7A11/GPX4信号通路保护心肌免受I/R损伤[56] Nrf2/SLC7A11/GPX4 呼吸系统疾病 臭氧通过激活TRPA1诱导人体支气管上皮细胞和小鼠肺线粒体功能障碍，从而通过PI3K/Akt/OPA1轴导致铁死亡[57] PI3K/Akt，OPA1,
ACSL4，SLC7A11，GPX4，
TFR1，TRPA1神经系统疾病 臭氧可以通过NRF2/SLC7A11/GPX4 通路改善脑缺血再灌注损伤[58] ACSL4，SLC7A11，GPX4，
FTH1香烟烟雾 （CS） 生殖系统疾病 CS暴露损害卵巢卵泡储备可能是由于颗粒样细胞中的氧化还原失衡引起的[59] GPX1，Wnt10b， Gja1，Lama1，GPX4 
下载: 导出CSV
-
[1] COHEN A J, BRAUER M, BURNETT R, et al. Estimates and 25-year trends of the global burden of disease attributable to ambient air pollution: an analysis of data from the Global Burden of Diseases Study 2015[J]. Lancet,2017,389(10082):1907-1918. doi: 10.1016/S0140-6736(17)30505-6 [2] WORLD HEALTH O. World health statistics 2023: monitoring health for the SDGs, sustainable development goals[M]. Geneva: World Health Organization, 2023. [3] NIU Y, CHEN R J, XIA Y J, et al. Personal ozone exposure and respiratory inflammatory response: the role of DNA methylation in the arginase-nitric oxide synthase pathway[J]. Environmental Science & Technology,2018,52(15):8785-8791. [4] SUNIL V R, PATEL-VAYAS K, SHEN J L, et al. Classical and alternative macrophage activation in the lung following ozone-induced oxidative stress[J]. Toxicology and Applied Pharmacology,2012,263(2):195-202. doi: 10.1016/j.taap.2012.06.009 [5] XU K, YAO Y, LIU H J, et al. ITGB4 deficiency induces DNA damage by downregulating HDAC1 in airway epithelial cells under stress stimulation[J]. Pediatric Allergy and Immunology,2022,33(10):e13871. doi: 10.1111/pai.13871 [6] DUAN L J, DONG W T, GAO L C, et al. DNA strand break of lung cells in mice induced by short-term exposure to ozone[J]. Journal of Zhengzhou University (Medical Sciences),2015,50(2):181-184. [7] XIA Y J, NIU Y, CAI J, et al. Effects of personal short-term exposure to ambient ozone on blood pressure and vascular endothelial function: a mechanistic study based on DNA methylation and metabolomics[J]. Environmental Science & Technology,2018,52(21):12774-12782. [8] THANGAVEL P, PARK D, LEE Y C. Recent insights into particulate matter (PM2.5)-mediated toxicity in humans: an overview[J]. International Journal of Environmental Research and Public Health,2022,19(12):7511. doi: 10.3390/ijerph19127511 [9] JOMOVA K, RAPTOVA R, ALOMAR S Y, et al. Reactive oxygen species, toxicity, oxidative stress, and antioxidants: chronic diseases and aging[J]. Archives of Toxicology,2023,97:2499-2574. doi: 10.1007/s00204-023-03562-9 [10] VOTER K Z, WHITIN J C, TORRES A, et al. Ozone exposure and the production of reactive oxygen species by bronchoalveolar cells in humans[J]. Inhalation Toxicology,2001,13(6):465-483. doi: 10.1080/08958370117715 [11] JIN Y F, FENG F F, DUAN L J, et al. Effects of ambient ozone on human respiratory system[J]. Chinese Journal of Public Health,2015,31(5):685-689. [12] DIXON S J, LEMBERG K M, LAMPRECHT M R, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death[J]. Cell,2012,149(5):1060-1072. doi: 10.1016/j.cell.2012.03.042 [13] XIE Y, HOU W, SONG X, et al. Ferroptosis: process and function[J]. Cell Death & Differentiation,2016,23(3):369-379. [14] DIXON S J, STOCKWELL B R. The role of iron and reactive oxygen species in cell death[J]. Nature Chemical Biology,2014,10:9-17. doi: 10.1038/nchembio.1416 [15] STOCKWELL B R, ANGELI J P F, BAYIR H, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease[J]. Cell,2017,171(2):273-285. doi: 10.1016/j.cell.2017.09.021 [16] ZHENG X G, JIN X D, YE F, et al. Ferroptosis: a novel regulated cell death participating in cellular stress response, radiotherapy, and immunotherapy[J]. Experimental Hematology & Oncology,2023,12(1):65. [17] STOCKWELL B R, JIANG X J. A physiological function for ferroptosis in tumor suppression by the immune system[J]. Cell Metabolism,2019,30(1):14-15. doi: 10.1016/j.cmet.2019.06.012 [18] KUANG F M, LIU J, TANG D L, et al. Oxidative damage and antioxidant defense in ferroptosis[J]. Frontiers in Cell and Developmental Biology,2020,8:586578. doi: 10.3389/fcell.2020.586578 [19] GALY B, CONRAD M, MUCKENTHALER M. Mechanisms controlling cellular and systemic iron homeostasis[J]. Nature Reviews Molecular Cell Biology,2024,25:133-155. doi: 10.1038/s41580-023-00648-1 [20] AYALA A, MUÑOZ M F, ARGÜELLES S. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal[J]. Oxidative Medicine and Cellular Longevity,2014,2014:360438. [21] KAGAN V E, MAO G W, QU F, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis[J]. Nature Chemical Biology,2017,13:81-90. doi: 10.1038/nchembio.2238 [22] VON KRUSENSTIERN A N, ROBSON R N, QIAN N, et al. Identification of essential sites of lipid peroxidation in ferroptosis[J]. Nature Chemical Biology,2023,19(6):719-30. doi: 10.1038/s41589-022-01249-3 [23] POPE L E, DIXON S J. Regulation of ferroptosis by lipid metabolism[J]. Trends in Cell Biology,2023,33(12):1077-1087. doi: 10.1016/j.tcb.2023.05.003 [24] KIM J W, LEE J Y, OH M, et al. An integrated view of lipid metabolism in ferroptosis revisited via lipidomic analysis[J]. Experimental & Molecular Medicine,2023,55:1620-1631. [25] YANG W S, KIM K J, GASCHLER M M, et al. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis[J]. Proceedings of the National Academy of Sciences of the United States of America,2016,113(34):E4966-E4975. [26] MAGTANONG L, KO P J, TO M, et al. Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state[J]. Cell Chemical Biology, 2019, 26(3): 420-432. e9. [27] MAGTANONG L, MUELLER G D, WILLIAMS K J, et al. Context-dependent regulation of ferroptosis sensitivity[J]. Cell Chemical Biology, 2022, 29(9): 1409-1418. [28] STOCKWELL B R. Ferroptosis turns 10: emerging mechanisms, physiological functions, and therapeutic applications[J]. Cell,2022,185(14):2401-2421. doi: 10.1016/j.cell.2022.06.003 [29] SATO H, TAMBA M, ISHII T, et al. Cloning and expression of a plasma membrane cystine/glutamate exchange transporter composed of two distinct proteins[J]. The Journal of Biological Chemistry,1999,274(17):11455-11458. doi: 10.1074/jbc.274.17.11455 [30] MUSGRAVE W B, YI H, KLINE D, et al. Probing the origins of glutathione biosynthesis through biochemical analysis of glutamate-cysteine ligase and glutathione synthetase from a model photosynthetic prokaryote[J]. The Biochemical Journal,2013,450(1):63-72. doi: 10.1042/BJ20121332 [31] KENNEDY L, SANDHU J K, HARPER M E, et al. Role of glutathione in cancer: from mechanisms to therapies[J]. Biomolecules,2020,10(10):1429. doi: 10.3390/biom10101429 [32] FRIEDMANN ANGELI J P, CONRAD M. Selenium and GPX4, a vital symbiosis[J]. Free Radical Biology & Medicine,2018,127:153-159. [33] WANG Y M, HU J, WU S, et al. Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases[J]. Signal Transduction and Targeted Therapy,2023,8(1):449. doi: 10.1038/s41392-023-01720-0 [34] WANG H, LIU C, ZHAO Y X, et al. Mitochondria regulation in ferroptosis[J]. European Journal of Cell Biology,2020,99(1):151058. doi: 10.1016/j.ejcb.2019.151058 [35] MURPHY M P. How mitochondria produce reactive oxygen species[J]. The Biochemical Journal,2009,417(1):1-13. doi: 10.1042/BJ20081386 [36] BELAVGENI A, TONNUS W, LINKERMANN A. Cancer cells evade ferroptosis: sex hormone-driven membrane-bound O-acyltransferase domain-containing 1 and 2 (MBOAT1/2) expression[J]. Signal Transduction and Targeted Therapy,2023,8:336. doi: 10.1038/s41392-023-01593-3 [37] LIANG D G, FENG Y, ZANDKARIMI F, et al. Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones[J]. Cell, 2023, 186(13): 2748-2764. e22. [38] ZHANG Y, JIANG M L, XIONG Y, et al. Integrated analysis of ATAC-seq and RNA-seq unveils the role of ferroptosis in PM2.5-induced asthma exacerbation[J]. International Immunopharmacology, 2023, 125(Pt B): 111209. [39] AHN Y, YIM Y H, YOO H M. Particulate matter induces oxidative stress and ferroptosis in human lung epithelial cells[J]. Toxics,2024,12(2):161. doi: 10.3390/toxics12020161 [40] YIN B W, REN J Y, CUI Q Q, et al. Astaxanthin alleviates fine particulate matter (PM2.5)-induced lung injury in rats by suppressing ferroptosis and apoptosis[J]. Food & Function,2023,14(24):10841-10854. [41] LEE K Y, YANG C C, SHUENG P W, et al. Downregulation of TAZ elicits a mitochondrial redox imbalance and ferroptosis in lung epithelial cells exposed to diesel exhaust particles[J]. Ecotoxicology and Environmental Safety,2023,266:115555. doi: 10.1016/j.ecoenv.2023.115555 [42] WANG Y L, ZHAO S J, JIA N, et al. Pretreatment with rosavin attenuates PM2.5-induced lung injury in rats through antiferroptosis via PI3K/Akt/Nrf2 signaling pathway[J]. Phytotherapy Research: PTR,2023,37(1):195-210. doi: 10.1002/ptr.7606 [43] WANG Y, DUAN H F, ZHANG J, et al. YAP1 protects against PM2.5-induced lung toxicity by suppressing pyroptosis and ferroptosis[J]. Ecotoxicology and Environmental Safety,2023,253:114708. doi: 10.1016/j.ecoenv.2023.114708 [44] YAN K, HOU T H, ZHU L Y, et al. PM2.5 inhibits system Xc- activity to induce ferroptosis by activating the AMPK-Beclin1 pathway in acute lung injury[J]. Ecotoxicology and Environmental Safety,2022,245:114083. doi: 10.1016/j.ecoenv.2022.114083 [45] ZHU M C, WANG J, CHEN C C, et al. Transcriptomic analysis of key genes and pathways in human bronchial epithelial cells BEAS-2B exposed to urban particulate matter[J]. Environmental Science and Pollution Research International,2021,28(8):9598-9609. doi: 10.1007/s11356-020-11347-1 [46] LI L P, PEI Z J, WU R T, et al. FDX1 regulates leydig cell ferroptosis mediates PM2.5-induced testicular dysfunction of mice[J]. Ecotoxicology and Environmental Safety,2023,263:115309. doi: 10.1016/j.ecoenv.2023.115309 [47] WANG Y L, SHEN Z R, ZHAO S J, et al. Sipeimine ameliorates PM2.5-induced lung injury by inhibiting ferroptosis via the PI3K/Akt/Nrf2 pathway: a network pharmacology approach[J]. Ecotoxicology and Environmental Safety,2022,239:113615. doi: 10.1016/j.ecoenv.2022.113615 [48] HU H F, LI L P, ZHANG H X, et al. Mechanism of YY1 mediating autophagy dependent ferroptosis in PM2.5 induced cardiac fibrosis[J]. Chemosphere,2023,315:137749. doi: 10.1016/j.chemosphere.2023.137749 [49] REN J Y, YIN B W, GUO Z H, et al. Astaxanthin alleviates PM2.5-induced cardiomyocyte injury via inhibiting ferroptosis[J]. Cellular & Molecular Biology Letters,2023,28(1):95. [50] MEI H Y, WU D Q, YONG Z H, et al. PM2.5 exposure exacerbates seizure symptoms and cognitive dysfunction by disrupting iron metabolism and the Nrf2-mediated ferroptosis pathway[J]. Science of the Total Environment,2024,910:168578. doi: 10.1016/j.scitotenv.2023.168578 [51] GUO C C, LYU Y, XIA S S, et al. Organic extracts in PM2.5 are the major triggers to induce ferroptosis in SH-SY5Y cells[J]. Ecotoxicology and Environmental Safety,2023,249:114350. doi: 10.1016/j.ecoenv.2022.114350 [52] GU Y Z, HAO S J, LIU K Y, et al. Airborne fine particulate matter (PM2.5) damages the inner blood-retinal barrier by inducing inflammation and ferroptosis in retinal vascular endothelial cells[J]. Science of the Total Environment, 2022, 838(Pt 4): 156563. [53] WANG J K, ZHANG Z H, SHI F Q, et al. PM2.5 caused ferroptosis in spermatocyte via overloading iron and disrupting redox homeostasis[J]. Science of the Total Environment,2023,872:162089. doi: 10.1016/j.scitotenv.2023.162089 [54] LIU X, AI Y Y, XIAO M C, et al. PM2.5 juvenile exposure-induced spermatogenesis dysfunction by triggering testes ferroptosis and antioxidative vitamins intervention in adult male rats[J]. Environmental Science and Pollution Research International,2023,30(51):111051-111061. doi: 10.1007/s11356-023-30150-2 [55] PARK M, CHO Y L, CHOI Y, et al. Particulate matter induces ferroptosis by accumulating iron and dysregulating the antioxidant system[J]. BMB Reports,2023,56(2):96-101. doi: 10.5483/BMBRep.2022-0139 [56] DING S Y, DUANMU X Y, XU L S, et al. Ozone pretreatment alleviates ischemiareperfusion injury-induced myocardial ferroptosis by activating the Nrf2/Slc7a11/Gpx4 axis[J]. Biomedicine & Pharmacotherapy,2023,165:115185. [57] WENG J L, LIU Q, LI C F, et al. TRPA1-PI3K/Akt-OPA1-ferroptosis axis in ozone-induced bronchial epithelial cell and lung injury[J]. Science of the Total Environment,2024,918:170668. doi: 10.1016/j.scitotenv.2024.170668 [58] ZHU F R, DING S Y, LIU Y, et al. Ozone-mediated cerebral protection: Unraveling the mechanism through ferroptosis and the NRF2/SLC7A11/GPX4 signaling pathway[J]. Journal of Chemical Neuroanatomy,2024,136:102387. doi: 10.1016/j.jchemneu.2023.102387 [59] LI F, WANG Y, XU M T, et al. Single-nucleus RNA Sequencing reveals the mechanism of cigarette smoke exposure on diminished ovarian reserve in mice[J]. Ecotoxicology and Environmental Safety,2022,245:114093. doi: 10.1016/j.ecoenv.2022.114093 [60] WANG G H, ZHEN L Y, LÜ P, et al. Effects of ozone and fine particulate matter (PM2.5) on rat cardiac autonomic nervous system and systemic inflammation[J]. Journal of Hygiene Research,2013,42(4):554-560. [61] ZANOBETTI A, DOMINICI F, WANG Y, et al. A national case-crossover analysis of the short-term effect of PM2.5 on hospitalizations and mortality in subjects with diabetes and neurological disorders[J]. Environmental Health,2014,13(1):38. doi: 10.1186/1476-069X-13-38 [62] CHEN H, BURNETT R T, KWONG J C, et al. Risk of incident diabetes in relation to long-term exposure to fine particulate matter in Ontario, Canada[J]. Environmental Health Perspectives,2013,121(7):804-810. doi: 10.1289/ehp.1205958 [63] WEICHENTHAL S A, GODRI-POLLITT K, VILLENEUVE P J. PM2.5, oxidant defence and cardiorespiratory health: a review[J]. Environmental Health,2013,12:40. doi: 10.1186/1476-069X-12-40 [64] HOU T H, ZHU L Y, WANG Y S, et al. Oxidative stress is the pivot for PM2.5-induced lung injury[J]. Food and Chemical Toxicology,2024,184:114362. doi: 10.1016/j.fct.2023.114362 [65] 郭少娟, 张元元, 王菲菲, 等. 大气颗粒物对斑马鱼胚胎的毒性及机制研究进展[J]. 环境工程技术学报,2020,10(3):338-345. doi: 10.12153/j.issn.1674-991X.20190155GUO S J, ZHANG Y Y, WANG F F, et al. A review of toxicity and mechanism of atmospheric particulate matter on zebrafish embryos[J]. Journal of Environmental Engineering Technology,2020,10(3):338-345. doi: 10.12153/j.issn.1674-991X.20190155 [66] 曾晨, 郭少娟, 杨立新. 汞、镉、铅、砷单一和混合暴露的毒性效应及机理研究进展[J]. 环境工程技术学报,2018,8(2):221-230. doi: 10.3969/j.issn.1674-991X.2018.02.030ZENG C, GUO S J, YANG L X. Toxic effects and mechanisms of exposure to single and mixture of mercury, cadmium, lead and arsenic[J]. Journal of Environmental Engineering Technology,2018,8(2):221-230. doi: 10.3969/j.issn.1674-991X.2018.02.030 [67] PIAO M J, AHN M J, KANG K A, et al. Particulate matter 2.5 damages skin cells by inducing oxidative stress, subcellular organelle dysfunction, and apoptosis[J]. Archives of Toxicology,2018,92(6):2077-2091. doi: 10.1007/s00204-018-2197-9 [68] WANG G H, JIANG R F, ZHAO Z H, et al. Effects of ozone and fine particulate matter (PM2.5) on rat system inflammation and cardiac function[J]. Toxicology Letters,2013,217(1):23-33. doi: 10.1016/j.toxlet.2012.11.009 [69] LI N, XIONG R, LI G R, et al. PM2.5 contributed to pulmonary epithelial senescence and ferroptosis by regulating USP3-SIRT3-P53 axis[J]. Free Radical Biology & Medicine,2023,205:291-304. [70] EVANS M D, DIZDAROGLU M, COOKE M S. Oxidative DNA damage and disease: induction, repair and significance[J]. Mutation Research,2004,567(1):1-61. doi: 10.1016/j.mrrev.2003.11.001 [71] SUNIL V R, VAYAS K N, MASSA C B, et al. Ozone-induced injury and oxidative stress in bronchiolar epithelium are associated with altered pulmonary mechanics[J]. Toxicological Sciences: an Official Journal of the Society of Toxicology,2013,133(2):309-319. doi: 10.1093/toxsci/kft071 [72] LI F, WIEGMAN C, SEIFFERT J M, et al. Effects of N-acetylcysteine in ozone-induced chronic obstructive pulmonary disease model[J]. PLoS One,2013,8(11):e80782. doi: 10.1371/journal.pone.0080782 [73] CHO H Y, GLADWELL W, YAMAMOTO M, et al. Exacerbated airway toxicity of environmental oxidant ozone in mice deficient in Nrf2[J]. Oxidative Medicine and Cellular Longevity,2013,2013:254069. ⊕ -
下载:
点击查看大图
图(1) / 表(1)
计量
- 文章访问数: 81
- HTML全文浏览量: 26
- PDF下载量: 5
- 被引次数: 0
