Journal of Otolaryngology and Ophthalmology of Shandong University ›› 2023, Vol. 37 ›› Issue (6): 24-32.doi: 10.6040/j.issn.1673-3770.0.2022.241

• Research Progress • Previous Articles     Next Articles

Role of ferroptosis in inflammatory diseases of the respiratory tract: a review of recent advances

SUN Xiwen, LUO Chunyu, LI Zhipeng, ZHANG Weitian   

  1. Department of Otorhinolaryngology & Head and Neck Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
  • Published:2023-12-15

Abstract: Ferroptosis is a form of programmed cell death characterized by the accumulation of iron-dependent lipid peroxides. In recent years, more studies have explored the mechanism of ferroptosis, identifying the crucial role of numerous molecules in its regulation. Emerging evidence has identified ferroptosis in various respiratory inflammatory diseases such as asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary infections, and even COVID-19, suggesting its crucial role in respiratory inflammatory disorders. Thus, drugs targeting the mechanism of ferroptosis may have significant therapeutic efficacy in respiratory inflammatory diseases. This review focused on the role and molecular mechanism of ferroptosis in respiratory inflammatory diseases, and proposed multi-angle regulation of ferroptosis as a promising potential strategy for their clinical treatment.

Key words: Ferroptosis, Asthma, Chronic obstructive pulmonary disease, Pneumonia, Nasal polyp, Allergic rhinitis

CLC Number: 

  • R56
[1] Chen X, Li JB, Kang R, et al. Ferroptosis: machinery and regulation[J]. Autophagy, 2021, 17(9): 2054-2081. doi:10.1080/15548627.2020.1810918
[2] Chen X, Kang R, Kroemer G, et al. Organelle-specific regulation of ferroptosis[J]. Cell Death Differ, 2021, 28(10): 2843-2856. doi:10.1038/s41418-021-00859-z
[3] Wang Y, Tang M. PM2.5 induces ferroptosis in human endothelial cells through iron overload and redox imbalance[J]. Environ Pollut, 2019, 254: 112937. doi:10.1016/j.envpol.2019.07.105
[4] Yoshida M, Minagawa S, Araya J, et al. Involvement of cigarette smoke-induced epithelial cell ferroptosis in COPD pathogenesis[J]. Nat Commun, 2019, 10(1): 3145. doi:10.1038/s41467-019-10991-7
[5] Huang CL, Yang MC, Deng J, et al. Upregulation and activation of p53 by erastininduced reactive oxygen species contribute to cytotoxic and cytostatic effects in A549 lung cancer cells[J]. Oncol Rep, 2018, 40(4): 2363-2370. doi:10.3892/or.2018.6585
[6] Dixon SJ, Lemberg KM, Lamprecht MR, 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
[7] Stockwell BR, Friedmann Angeli JP, 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
[8] Jiang XJ, Stockwell BR, 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
[9] Zhao JM, Dar HH, Deng YH, et al. PEBP1 acts as a rheostat between prosurvival autophagy and ferroptotic death in asthmatic epithelial cells[J]. Proc Natl Acad Sci USA, 2020, 117(25): 14376-14385. doi:10.1073/pnas.1921618117
[10] Anthonymuthu TS, Tyurina YY, Sun WY, et al. Resolving the paradox of ferroptotic cell death: Ferrostatin-1 binds to 15LOX/PEBP1 complex, suppresses generation of peroxidized ETE-PE, and protects against ferroptosis[J]. Redox Biol, 2021, 38: 101744. doi:10.1016/j.redox.2020.101744
[11] Doll S, Conrad M. Iron and ferroptosis: a still ill-defined liaison[J]. IUBMB Life, 2017, 69(6): 423-434. doi:10.1002/iub.1616
[12] Stoyanovsky DA, Tyurina YY, Shrivastava I, et al. Iron catalysis of lipid peroxidation in ferroptosis: regulated enzymatic or random free radical reaction? [J]. Free Radic Biol Med, 2019, 133: 153-161. doi:10.1016/j.freeradbiomed.2018.09.008
[13] Yan HF, Zou T, Tuo QZ, et al. Ferroptosis: mechanisms and links with diseases[J]. Signal Transduct Target Ther, 2021, 6(1): 49. doi:10.1038/s41392-020-00428-9
[14] Wang XT, Wang ZX, Cao J, et al. Ferroptosis mechanisms involved in hippocampal-related diseases[J]. Int J Mol Sci, 2021, 22(18): 9902. doi:10.3390/ijms22189902
[15] Ingold I, Berndt C, Schmitt S, et al. Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis[J]. Cell, 2018, 172(3): 409-422.e21. doi:10.1016/j.cell.2017.11.048
[16] Alim I, Caulfield JT, Chen YX, et al. Selenium drives a transcriptional adaptive program to block ferroptosis and treat stroke[J]. Cell, 2019, 177(5): 1262-1279.e25. doi:10.1016/j.cell.2019.03.032
[17] Yang WS, SriRamaratnam R, Welsch ME, et al. Regulation of ferroptotic cancer cell death by GPX4[J]. Cell, 2014, 156(1/2): 317-331. doi:10.1016/j.cell.2013.12.010
[18] Koppula P, Zhuang L, Gan BY. Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy[J]. Protein Cell, 2021, 12(8): 599-620. doi:10.1007/s13238-020-00789-5
[19] Gao W, Li LL, Wang YJ, et al. Bronchial epithelial cells: the key effector cells in the pathogenesis of chronic obstructive pulmonary disease? [J]. Respirology, 2015, 20(5): 722-729. doi:10.1111/resp.12542
[20] 黄丹怡, 张婷, 陈静, 等. 上皮屏障在慢性鼻窦炎伴鼻息肉中的研究进展[J]. 山东大学耳鼻喉眼学报, 2022, 36(3): 78-83. doi:10.6040/j.issn.1673-3770.0.2021.583 HUANG Danyi, ZHANG Ting, CHEN Jing, et al. Progress of research regarding the role of the epithelial barrier in chronic rhinosinusitis with nasal polyps[J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2022, 36(3): 78-83. doi:10.6040/j.issn.1673-3770.0.2021.583
[21] Kim N, Han D, Wang IJ, et al. Altered secretome by diesel exhaust particles and lipopolysaccharide in primary human nasal epithelium[J]. J Allergy Clin Immunol, 2022, 149(6): 2126-2138. doi:10.1016/j.jaci.2021.12.793
[22] Lugg ST, Scott A, Parekh D, et al. Cigarette smoke exposure and alveolar macrophages: mechanisms for lung disease[J]. Thorax, 2022, 77(1): 94-101. doi:10.1136/thoraxjnl-2020-216296
[23] Krysko O, Holtappels G, Zhang N, et al. Alternatively activated macrophages and impaired phagocytosis of S. aureus in chronic rhinosinusitis[J]. Allergy, 2011, 66(3): 396-403. doi:10.1111/j.1398-9995.2010.02498.x
[24] Li JY, Yao YM, Tian YP. Ferroptosis: a trigger of proinflammatory state progression to immunogenicity in necroinflammatory disease[J]. Front Immunol, 2021, 12: 701163. doi:10.3389/fimmu.2021.701163
[25] Cheng Y, Song YT, Chen H, et al. Ferroptosis mediated by lipid reactive oxygen species: a possible causal link of neuroinflammation to neurological disorders[J]. Oxid Med Cell Longev, 2021: 5005136. doi:10.1155/2021/5005136
[26] 李贝, 田首元, 郭志佳, 等. 铁死亡与炎症性疾病的研究现状[J]. 医学综述, 2021, 27(7): 1302-1306. doi: 10.3969/j.issn.1006-2084.2021.07.010 LI Bei, TIAN Shouyuan, GUO Zhijia, et al. Research status of ferroptosis and inflammatory diseases[J]. Medical Recapitulate, 2021, 27(7): 1302-1306. doi: 10.3969/j.issn.1006-2084.2021.07.010
[27] 中华医学会呼吸病学分会哮喘学组. 上-下气道慢性炎症性疾病联合诊疗与管理专家共识[J]. 中华医学杂志, 2017, 97(26): 2001-2022. doi:10.3760/cma.j.issn.0376-2491.2017.26.001
[28] 王娜, 柴向斌. 前列腺源性ETS因子在哮喘及鼻黏膜炎性疾病中的研究进展[J]. 山东大学耳鼻喉眼学报, 2022, 36(3): 136-141. doi: 10.6040/j.issn.1673-3770.0.2020.498 WANG Na, CHAI Xiangbin. Research progress on prostate-derived ETS factor in asthma and inflammatory diseases of the nasal mucosa[J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2022, 36(3): 136-141. doi: 10.6040/j.issn.1673-3770.0.2020.498
[29] Akar-Ghibril N, Casale T, Custovic A, et al. Allergic endotypes and phenotypes of asthma[J]. J Allergy Clin Immunol Pract, 2020, 8(2): 429-440. doi:10.1016/j.jaip.2019.11.008
[30] Wenzel SE, Tyurina YY, Zhao JM, et al. PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals[J]. Cell, 2017, 171(3): 628-641.e26. doi:10.1016/j.cell.2017.09.044
[31] Nagasaki T, Schuyler AJ, Zhao J, et al. 15LO1 dictates glutathione redox changes in asthmatic airway epithelium to worsen type 2 inflammation[J]. J Clin Invest, 2022, 132(1): e151685. doi:10.1172/jci151685
[32] Yamada K, St Croix CM, Deng Y, et al. 15 lipoxygenase linked mitophagy promotes epithelial cell mitochondrial loss in type-2 hi asthma[C] //D12. BASIC SCIENCE INSIGHTS INTO MODULATION OF IMMUNE AND INFLAMMATORY PATHWAYS. American Thoracic Society, 2022. doi:10.1164/ajrccm-conference.2022.205.1_meetingabstracts.a5009
[33] Banerjee P, Balraj P, Ambhore NS, et al. Network and co-expression analysis of airway smooth muscle cell transcriptome delineates potential gene signatures in asthma[J]. Sci Rep, 2021, 11(1): 14386. doi:10.1038/s41598-021-93845-x
[34] Tang WF, Dong M, Teng FZ, et al. Environmental allergens house dust mite-induced asthma is associated with ferroptosis in the lungs[J]. Exp Ther Med, 2021, 22(6): 1483. doi:10.3892/etm.2021.10918
[35] Han F, Li SJ, Yang YK, et al. Interleukin-6 promotes ferroptosis in bronchial epithelial cells by inducing reactive oxygen species-dependent lipid peroxidation and disrupting iron homeostasis[J]. Bioengineered, 2021, 12(1): 5279-5288. doi:10.1080/21655979.2021.1964158
[36] Yang N, Shang Y. Ferrostatin-1 and 3-methyladenine ameliorate ferroptosis in OVA-induced asthma model and in IL-13-challenged BEAS-2B cells[J]. Oxid Med Cell Longev, 2022: 9657933. doi:10.1155/2022/9657933
[37] Wu YP, Chen HX, Xuan NX, et al. Induction of ferroptosis-like cell death of eosinophils exerts synergistic effects with glucocorticoids in allergic airway inflammation[J]. Thorax, 2020, 75(11): 918-927. doi:10.1136/thoraxjnl-2020-214764
[38] Lin ZW, Xu YF, Guan LL, et al. Seven ferroptosis-specific expressed genes are considered as potential biomarkers for the diagnosis and treatment of cigarette smoke-induced chronic obstructive pulmonary disease[J]. Ann Transl Med, 2022, 10(6): 331. doi:10.21037/atm-22-1009
[39] Lian NF, Zhang QX, Chen J, et al. The role of ferroptosis in bronchoalveolar epithelial cell injury induced by cigarette smoke extract[J]. Front Physiol, 2021, 12: 751206. doi:10.3389/fphys.2021.751206
[40] Ghio AJ, Hilborn ED, Stonehuerner JG, et al. Particulate matter in cigarette smoke alters iron homeostasis to produce a biological effect[J]. Am J Respir Crit Care Med, 2008, 178(11): 1130-1138. doi:10.1164/rccm.200802-334OC
[41] Liu JX, Zhang ZX, Yang Y, et al. NCOA4-mediated ferroptosis in bronchial epithelial cells promotes macrophage M2 polarization in COPD emphysema[J]. Int J Chron Obstruct Pulmon Dis, 2022, 17: 667-681. doi:10.2147/COPD.S354896
[42] Jeridi A, Günes Günsel G, Novikova M, et al. Macrophage induced ferroptotic cell death of epithelial cells drives COPD pathogenesis[C/OL] //A17. COPD: SINGLE CELL RNA SEQUENCING, EPIGENETICS, MODELS, AND MACROPHAGES. American Thoracic Society:[S.l.] , 2022. doi:10.1164/ajrccm-conference.2022.205.1_meetingabstracts.a1038
[43] Wang Y, Liao S, Pan ZH, et al. Hydrogen sulfide alleviates particulate matter-induced emphysema and airway inflammation by suppressing ferroptosis[J]. Free Radic Biol Med, 2022, 186: 1-16. doi:10.1016/j.freeradbiomed.2022.04.014
[44] Zhang ZX, Fu CL, Liu JX, et al. Hypermethylation of the Nrf2 promoter induces ferroptosis by inhibiting the Nrf2-GPX4 axis in COPD[J]. Int J Chron Obstruct Pulmon Dis, 2021, 16: 3347-3362. doi:10.2147/COPD.S340113
[45] Stockwell BR, Jiang XJ, Gu W. Emerging mechanisms and disease relevance of ferroptosis[J]. Trends Cell Biol, 2020, 30(6): 478-490. doi:10.1016/j.tcb.2020.02.009
[46] Dar HH, Tyurina YY, Mikulska-Ruminska K, et al. Pseudomonas aeruginosa utilizes host polyunsaturated phosphatidylethanolamines to trigger theft-ferroptosis in bronchial epithelium[J]. J Clin Invest, 2018, 128(10): 4639-4653. doi:10.1172/JCI99490
[47] Amaral EP, Costa DL, Namasivayam S, et al. A major role for ferroptosis in Mycobacterium tuberculosis-induced cell death and tissue necrosis[J]. J Exp Med, 2019, 216(3): 556-570. doi:10.1084/jem.20181776
[48] Habib HM, Ibrahim S, Zaim A, et al. The role of iron in the pathogenesis of COVID-19 and possible treatment with lactoferrin and other iron chelators[J]. Biomedecine Pharmacother, 2021, 136: 111228. doi:10.1016/j.biopha.2021.111228
[49] Yang M, Lai CL. SARS-CoV-2 infection: can ferroptosis be a potential treatment target for multiple organ involvement? [J]. Cell Death Discov, 2020, 6: 130. doi:10.1038/s41420-020-00369-w
[50] Li JC, Lu KM, Sun FL, 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
[51] He RY, Liu BH, Xiong R, et al. Itaconate inhibits ferroptosis of macrophage via Nrf2 pathways against Sepsis-induced acute lung injury[J]. Cell Death Discov, 2022, 8(1): 43. doi:10.1038/s41420-021-00807-3
[52] Liu X, Wang L, Xing QZ, et al. Sevoflurane inhibits ferroptosis: a new mechanism to explain its protective role against lipopolysaccharide-induced acute lung injury[J]. Life Sci, 2021, 275: 119391. doi:10.1016/j.lfs.2021.119391
[53] Liu PF, Feng YT, Li HW, et al. Ferrostatin-1 alleviates lipopolysaccharide-induced acute lung injury via inhibiting ferroptosis[J]. Cell Mol Biol Lett, 2020, 25: 10. doi:10.1186/s11658-020-00205-0
[54] 蒋捍东, 陈碧. 间质性肺疾病的再认识[J]. 中华医学杂志, 2021, 101(20): 1453-1457. doi:10.3760/cma.j.cn112137-2020831-02514 JIANG Handong, CHEN Bi. Interstitial lung disease revisited[J]. National Medical Journal of China, 2021, 101(20): 1453-1457. doi:10.3760/cma.j.cn112137-2020831-02514
[55] He J, Li X, Yu M. Bioinformatics analysis identifies potential ferroptosis key genes in the pathogenesis of pulmonary fibrosis[J]. Front Genet, 2021, 12: 788417. doi:10.3389/fgene.2021.788417
[56] Li YP, Ning SW, Yang Y, et al. A ferroptosis-related gene signature for lung function and quality of life in patients with idiopathic pulmonary fibrosis[All Fields].2021
[57] Gong Y, Wang N, Liu NG, et al. Lipid peroxidation and GPX4 inhibition are common causes for myofibroblast differentiation and ferroptosis[J]. DNA Cell Biol, 2019, 38(7): 725-733. doi:10.1089/dna.2018.4541
[58] Liu X, Zhang JQ, Xie W. The role of ferroptosis in acute lung injury[J]. Mol Cell Biochem, 2022, 477(5): 1453-1461. doi:10.1007/s11010-021-04327-7
[59] Liu TY, Bao R, Wang QS, et al. SiO2-induced ferroptosis in macrophages promotes the development of pulmonary fibrosis in silicosis models[J]. Toxicol Res, 2021, 11(1): 42-51. doi:10.1093/toxres/tfab105
[60] Persson HL. Iron-dependent lysosomal destabilization initiates silica-induced apoptosis in murine macrophages[J]. Toxicol Lett, 2005, 159(2): 124-133. doi:10.1016/j.toxlet.2005.05.002
[61] Takahashi M, Mizumura K, Gon Y, et al. Iron-dependent mitochondrial dysfunction contributes to the pathogenesis of pulmonary fibrosis[J]. Front Pharmacol, 2021, 12: 643980. doi:10.3389/fphar.2021.643980
[62] Yao Y, Chen CL, Yu D, et al. Roles of follicular helper and regulatory T cells in allergic diseases and allergen immunotherapy[J]. Allergy, 2021, 76(2): 456-470. doi:10.1111/all.14639
[63] 黄嘉莉, 杨淑荣. 变应性鼻炎中信号传导通路的研究进展[J]. 山东大学耳鼻喉眼学报, 2020, 34(4): 125-129. doi:10.6040/j.issn.1673-3770.0.2019.355 HUANG Jiali, YANG Shurong. Advances in research on related signaling pathways in allergic rhinitis[J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2020, 34(4): 125-129. doi:10.6040/j.issn.1673-3770.0.2019.355
[64] Yao Y, Chen ZA, Zhang H, et al. Selenium-GPX4 axis protects follicular helper T cells from ferroptosis[J]. Nat Immunol, 2021, 22(9): 1127-1139. doi:10.1038/s41590-021-00996-0
[65] Yu SJ, Jia JQ, Zheng JY, et al. Recent progress of ferroptosis in lung diseases[J]. Front Cell Dev Biol, 2021, 9: 789517. doi:10.3389/fcell.2021.789517
[1] FENG Sicong, YU Xiaolan, LOU Dan. Evaluation of the effect of Messerklinger middle turbinate plasty on chronic rhinosinusitis with nasal polyps based on the expression of Ki67 and GM-CSF in vesicular tissue [J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2026, 40(3): 31-39.
[2] LYU Qian, TANG Yuan, GU Zijun, SHI Sailei, LIU Ping, WAN Wenjin. Current status of benefit finding among patients with allergic rhinitis and its influence factors [J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2026, 40(1): 21-28.
[3] GU Min, LU Meiping. Advances in the application of nanomedicine delivery systems in allergen immunotherapy for allergic rhinitis [J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2026, 40(1): 106-111.
[4] QIN Nana, LI Yufen, SUN Yuhao, WEI Jian, LI Qin. Effect of interleukin-13 receptor-α2 on nasal mucosal remodeling in rats with allergic rhinitis by TGF-β1/Smad signaling pathway [J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2025, 39(6): 71-77.
[5] DU Kangli, ZHENG Zhenyu, XU Zhanjiang, ZHANG Yu, CHEN Lu, LU Mengyao. Construction and validation of risk prediction model for nasal septal deviation complicated with chronic sinusitis [J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2025, 39(6): 78-86.
[6] XIONG Qin, ZHANG Yan, WU Rina, LI Feng, TANG Lixing. Application of intranasal corticosteroids in pediatrics [J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2025, 39(6): 160-167.
[7] XU Xuemeng, FAN Lei, YU Wangbo, JIANG Zhiyue, PAN Chen, HUANG Yongqin. Meta-analysis of the efficacy of omalizumab in combination with specific immunotherapy for allergic rhinitis [J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2025, 39(5): 26-33.
[8] HUANG Huan, HUA Hongli, DENG Yuqin, JIANG Chengyang, WANG Yuwei, YANG Xinghai. Correlation of allergic rhinitis, tonsil adenoid hypertrophy, and sinusitis in children and analysis of its clinical guiding value [J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2025, 39(5): 34-41.
[9] LIU Yijun, GU Yue, GUAN Dayu, YANG Yucheng, SHEN Yang. The long-term clinical efficacy and safety of vidian neurectomy in refractory allergic rhinitis [J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2025, 39(5): 42-48.
[10] ZHANG Jiaqi, YUAN Ye, HONG Chen, GU Min, CHENG Lei, LU Meiping. Mendelian randomization study of gut microbiota, chronic sinusitis, and nasal polyps: Causal relationships and metabolite-mediated effects [J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2025, 39(5): 49-60.
[11] ZHANG Ting, WANG Meilan, GAO Yingqin. Research progress of IL-35 in allergic rhinitis [J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2025, 39(5): 139-147.
[12] WANG Sheng, HUANG Xudong. Recent advancements in the research on ferroptosis and age-related cataracts [J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2025, 39(5): 161-168.
[13] ZHANG Zhuping, PENG Zican, XIAO Zhenlong, LI Cheng, YU Di, WANG Xinglong, CHEN Wei, Guo Bei. The value of a novel nasal secretion eosinophil cationic protein-myeloperoxidase test paper assay in allergic rhinitis [J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2025, 39(3): 129-134.
[14] ZHANG Guangling, CHEN Xingxue, WU Tianyi, SUN Zhanwei, WANG Weiwei, LI Shichao,WANG Guangke. The expression and function of Tespa1 in chronic rhinosinusitis with nasal polyps [J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2025, 39(2): 35-42.
[15] CAO Zhengyong, LI Xiaobo. Comparison of the safety and efficacy of short-course postoperative topical glucocorticoid adjuvant therapy for eCRSwNP combined with asthma [J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2025, 39(2): 43-50.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed   
No Suggested Reading articles found!