Molecular mechanism of paraquat-induced ferroptosis leading to pulmonary fibrosis mediated by Keap1/Nrf2 signaling pathway

Springer Science and Business Media LLC - Tập 50 - Trang 9249-9261 - 2023
Xiaoxia Yang1, Ping Xiao2, Xiaofeng Shi3
1Department of Neurology, Tianjin First Central Hospital, Tianjin, China
2Clinical Laboratory, Tianjin First Central Hospital, Tianjin, China
3Department of Emergency, Tianjin First Central Hospital, Tianjin, China

Tóm tắt

Paraquat (PQ) is a widely used and highly toxic pesticide that is often actively ingested and causes pulmonary fibrosis in patients. Ferroptosis is a regulated form of non-apoptotic cell death associated with iron-dependent lipid peroxidation. Previous studies have shown that ferroptosis is involved in the occurrence and development of acute lung injury (ALI). In this study, a model rat with inflammatory response, oxidative stress, lipid peroxidation, and pulmonary fibrosis was successfully established by PQ administration. The occurrence of ferroptosis in PQ model rats was confirmed by TUNEL staining, iron ion detection, and Ferroptosis related biomarkers detection. Western blotting (WB) and real-time PCR (RT-PCR) showed that the expression of Keap1 was significantly up-regulated and the expression of Nrf2 was significantly down-regulated in the lung tissue of PQ rats. Further transcriptomics and proteomics confirmed: (1) Enrichment of molecular processes related to iron ion binding; (2) Keap1 may promote Nrf2 ubiquitination and lead to Nrf2 degradation; (3) There is functional enrichment in ferroptosis related pathways. Our results suggest that PQ can regulate Keap1/Nrf2 signaling pathway, leading to increased lipid peroxidation and abnormal iron uptake, thereby inducing iron death and exacerbating the progression of pulmonary fibrosis. Our study provides new insights into PQ-induced pulmonary fibrosis.

Tài liệu tham khảo

Franco DSP, Georgin J, Lima EC, Silva LFO (2022) Advances made in removing paraquat herbicide by adsorption technology: a review. J Water Process Eng 49:102988. https://doi.org/10.1016/j.jwpe.2022.102988

Liu X, Yang H, Liu Z (2022) Signaling pathways involved in paraquat-induced pulmonary toxicity: molecular mechanisms and potential therapeutic drugs. Int Immunopharmacol 113:109301. https://doi.org/10.1016/j.intimp.2022.109301

Alizadeh S, Anani-sarab G, Amiri H, Hashemi M (2022) Paraquat induced oxidative stress, DNA damage, and cytotoxicity in lymphocytes. Heliyon 8(7):e09895. https://doi.org/10.1016/j.heliyon.2022.e09895

Marashi SM, Raji H, Nasri-Nasrabadi Z, Majidi M, Vasheghani-Farahani M, Abbaspour A, Ghorbani A, Vasigh S (2015) One-lung circumvention, an interventional strategy for pulmonary salvage in acute paraquat poisoning: an evidence-based review. Tzu Chi Medical Journal 27(3):99–101. https://doi.org/10.1016/j.tcmj.2015.06.002

Zheng Q, Zhang Y, Zhao Z, Shen H, Zhao H, Zhao M (2021) Isorhynchophylline ameliorates paraquat-induced acute kidney injury by attenuating oxidative stress and mitochondrial damage via regulating toll-interacting expression. Toxicol Appl Pharmcol 420:115521. https://doi.org/10.1016/j.taap.2021.115521

Yen T-H, Chang C-W, Tsai H-R, Fu J-F, Yen H-C (2022) Immunosuppressive therapies attenuate paraquat-induced renal dysfunction by suppressing inflammatory responses and lipid peroxidation. Free Radic Biol Med 191:249–260. https://doi.org/10.1016/j.freeradbiomed.2022.08.031

Oghabian Z, Williams J, Mohajeri M, Nakhaee S, Shojaeepour S, Amirabadizadeh A, Elhamirad S, Hajihosseini M, Mansouri B, Mehrpour O (2019) Clinical features, treatment, prognosis, and Mortality in Paraquat Poisonings: a hospital-based study in Iran. J Res Pharm Pract 8(3):129–136. https://doi.org/10.4103/jrpp.JRPP_18_71

Luo L, Huang F, Zhong S, Ding R, Su J, Li X (2022) Astaxanthin attenuates ferroptosis via Keap1-Nrf2/HO-1 signaling pathways in LPS-induced acute lung injury. Life Sci 311:121091. https://doi.org/10.1016/j.lfs.2022.121091

Koppula P, Lei G, Zhang Y, Yan Y, Mao C, Kondiparthi L, Shi J, Liu X, Horbath A, Das M, Li W, Poyurovsky MV, Olszewski K, Gan B (2022) A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers. Nat Commun 13(1):2206. https://doi.org/10.1038/s41467-022-29905-1

Tang D, Chen X, Kang R, Kroemer G (2021) Ferroptosis: molecular mechanisms and health implications. Cell Res 31(2):107–125. https://doi.org/10.1038/s41422-020-00441-1

Xin S, Schick JA (2023) PUFAs dictate the balance of power in ferroptosis. Cell Calcium 110:102703

Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascón S, Hatzios SK, Kagan VE, Noel K, Jiang X, Linkermann A, Murphy ME, Overholtzer M, Oyagi A, Pagnussat GC, Park J, Ran Q, Rosenfeld CS, Salnikow K, Tang D, Torti FM, Torti SV, Toyokuni S, Woerpel KA, Zhang DD (2017) Ferroptosis: a regulated cell death Nexus linking metabolism, Redox Biology, and Disease. Cell 171(2):273–285. https://doi.org/10.1016/j.cell.2017.09.021

Liu X, Wang L, Xing Q, Li K, Si J, Ma X, Mao L (2021) Sevoflurane inhibits ferroptosis: a new mechanism to explain its protective role against lipopolysaccharide-induced acute lung injury. Life Sci 275:119391. https://doi.org/10.1016/j.lfs.2021.119391

Rashidipour N, Karami-Mohajeri S, Mandegary A, Mohammadinejad R, Wong A, Mohit M, Salehi J, Ashrafizadeh M, Najafi A, Abiri A (2020) Where ferroptosis inhibitors and paraquat detoxification mechanisms intersect, exploring possible treatment strategies. Toxicology 433–434. https://doi.org/10.1016/j.tox.2020.152407

Xu W, Deng H, Hu S, Zhang Y, Zheng L, Liu M, Chen Y, Wei J, Yang H, Lv X (2021) Role of ferroptosis in Lung Diseases. J Inflamm Res 14:2079–2090. https://doi.org/10.2147/jir.s307081

Li X, Duan L, Yuan S, Zhuang X, Qiao T, He J (2019) Ferroptosis inhibitor alleviates Radiation-induced lung fibrosis (RILF) via down-regulation of TGF-β1. J Inflamm 16(1):11. https://doi.org/10.1186/s12950-019-0216-0

Ma T-L, Zhou Y, Wang C, Wang L, Chen J-X, Yang H-H, Zhang C-Y, Zhou Y, Guan C-X (2021) Targeting ferroptosis for Lung Diseases: exploring Novel Strategies in Ferroptosis-Associated Mechanisms, oxidative Medicine and Cellular Longevity 2021. 1098970. https://doi.org/10.1155/2021/1098970

Tai W, Deng S, Wu W, Li Z, Lei W, Wang Y, Vongphouttha C, Zhang T, Dong Z (2020) Rapamycin attenuates the paraquat-induced pulmonary fibrosis through activating Nrf2 pathway. J Cell Physiol 235(2):1759–1768. https://doi.org/10.1002/jcp.29094

Li J, Lu K, Sun F, Tan S, Zhang X, Sheng W, Hao W, Liu M, Lv W, Han W (2021) Panaxydol attenuates ferroptosis against LPS-induced acute lung injury in mice by Keap1-Nrf2/HO-1 pathway. J Translational Med 19(1):96. https://doi.org/10.1186/s12967-021-02745-1

Zhao Y, Lu J, Mao A, Zhang R, Guan S (2021) Autophagy inhibition plays a protective role in Ferroptosis Induced by Alcohol via the p62–Keap1–Nrf2 pathway. J Agric Food Chem 69(33):9671–9683. https://doi.org/10.1021/acs.jafc.1c03751

Piloni NE, Vargas R, Fernández V, Videla LA, Puntarulo S (2021) Effects of acute iron overload on Nrf2-related glutathione metabolism in rat brain. Biometals 34(5):1017–1027. https://doi.org/10.1007/s10534-021-00324-x

Fukushima T, Yamada K, Hojo N, Isobe A, Shiwaku K, Yamane Y (1994) Mechanism of cytotoxicity of paraquat: III. The effects of acute paraquat exposure on the electron transport system in rat mitochondria. Exp Toxicol Pathol 46(6):437–441. https://doi.org/10.1016/S0940-2993(11)80056-4

Shao M, Yang S, Zheng A, Wu Z, Chen M, Yao R, Shi Y, Chen G (2022) Pathophysiological changes in rhesus monkeys with paraquat-induced pulmonary fibrosis. Lung 200(5):549–560

Yu C, Xiao J-H (2021) The Keap1-Nrf2 system: a mediator between oxidative stress and aging, oxidative Medicine and Cellular Longevity 2021. 6635460. https://doi.org/10.1155/2021/6635460

Thanas C, Ziros PG, Chartoumpekis DV, Renaud CO, Sykiotis GP (2020) The Keap1/Nrf2 signaling pathway in the Thyroid—2020 Update. Antioxidants 9(11):1082

Guo Z, Mo Z (2020) Keap1-Nrf2 signaling pathway in angiogenesis and vascular diseases. J Tissue Eng Regen Med 14(6):869–883. https://doi.org/10.1002/term.3053

Zhang Z-D, Yang Y-J, Liu X-W, Qin Z, Li S-H, Li J-Y (2021) Aspirin eugenol ester ameliorates paraquat-induced oxidative damage through ROS/p38-MAPK-mediated mitochondrial apoptosis pathway. Toxicology 453:152721. https://doi.org/10.1016/j.tox.2021.152721

Song C-Y, Feng M-X, Li L, Wang P, Lu X, Lu Y-Q (2023) Tripterygium wilfordii Hook.f. Ameliorates paraquat-induced lung injury by reducing oxidative stress and ferroptosis via Nrf2/HO-1 pathway. Ecotoxicol Environ Saf 252:114575. https://doi.org/10.1016/j.ecoenv.2023.114575

Shahabadi N, Moshiri M, Roohbakhsh A, Imenshahidi M, Hashemi M, Amin F, Yazdian-Robati R, Salmasi Z, Etemad L (2022) A dose-related positive effect of inhaled simvastatin-loaded PLGA nanoparticles on paraquat-induced pulmonary fibrosis in rats. Basic Clin Pharmacol Toxicol 131(4):251–261. https://doi.org/10.1111/bcpt.13771

Fan L, Li Y, Zhang X, Wu Y, Song Y, Zhang F, Zhang J, Sun H (2022) Time-resolved proteome and transcriptome of paraquat-induced pulmonary fibrosis. Pulm Pharmacol Ther 75:102145. https://doi.org/10.1016/j.pupt.2022.102145

Suntres ZE (2018) Exploring the potential benefit of natural product extracts in paraquat toxicity. Fitoterapia 131:160–167. https://doi.org/10.1016/j.fitote.2018.10.026

Sun B, Chen YG (2016) Advances in the mechanism of paraquat-induced pulmonary injury. Eur Rev Med Pharmacol Sci 20(8):1597–1602

Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B 3rd, Stockwell BR (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149(5):1060–1072. https://doi.org/10.1016/j.cell.2012.03.042

Plascencia-Villa G, Perry G (2021) Role of ferroptosis iron-dependent cell death in neurodegenerative processes. Alzheimer’s Dement 17(3):e055243. https://doi.org/10.1002/alz.055243

Li Y, Zhong X, Ye J, Guo H, Long Y (2021) Proteome of Saccharomyces cerevisiae under paraquat stress regulated by therapeutic concentration of copper ions. Ecotoxicol Environ Saf 217:112245. https://doi.org/10.1016/j.ecoenv.2021.112245

Song Q, Peng S, Sun Z, Heng X, Zhu X (2021) Temozolomide drives ferroptosis via a DMT1-Dependent pathway in Glioblastoma cells. Yonsei Med J 62(9):843–849. https://doi.org/10.3349/ymj.2021.62.9.843

Turcu AL, Versini A, Khene N, Gaillet C, Cañeque T, Müller S, Rodriguez R (2020) DMT1 inhibitors kill Cancer Stem cells by blocking lysosomal Iron translocation. Chem – Eur J 26(33):7369–7373. https://doi.org/10.1002/chem.202000159

Jin J, Schorpp K, Samaga D, Unger K, Hadian K, Stockwell BR (2022) Machine learning classifies ferroptosis and apoptosis cell death modalities with TfR1 immunostaining. ACS Chem Biol 17(3):654–660. https://doi.org/10.1021/acschembio.1c00953

Cheng H, Wang P, Wang N, Dong W, Chen Z, Wu M, Wang Z, Yu Z, Guan D, Wang L, Zhao R (2023) Neuroprotection of NRF2 against ferroptosis after traumatic brain Injury in mice. Antioxidants 12(3):731

Yoshida GJ (2020) The interplay between apoptosis and ferroptosis mediated by ER stress. Apoptosis 25(11):784–785. https://doi.org/10.1007/s10495-020-01641-1

Forcina GC, Dixon SJ (2019) GPX4 at the Crossroads of Lipid Homeostasis and Ferroptosis, PROTEOMICS 19(18) 1800311. https://doi.org/10.1002/pmic.201800311

Dodson M, Castro-Portuguez R, Zhang DD (2019) NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol 23:101107. https://doi.org/10.1016/j.redox.2019.101107

Kansanen E, Kuosmanen SM, Leinonen H, Levonen A-L (2013) The Keap1-Nrf2 pathway: mechanisms of activation and dysregulation in cancer. Redox Biol 1(1):45–49. https://doi.org/10.1016/j.redox.2012.10.001

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