Correlation analysis and mechanism study of ferroptosis with pulmonary fibrosis_West China Medical Journal

Authors：

LIU Zhuo , ZHAO Zheng , ZHANG Liangliang ,  YANG Cuiying , JIN Zhao

Department of Thoracic Surgery Ⅰ , Handan Central Hospital, Handan, Hebei 056000, P. R. China;

Corresponding author：

YANG Cuiying, Email: 15333303295@163.com

Keywords：

Ferroptosis; pulmonary fibrosis; bioinformatic analysis

DOI：

10.7507/1002-0179.202310269

Video：

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Objective To explore the correlation and mechanism of ferroptosis with pulmonary fibrosis. Methods Pulmonary fibrosis tissue sequencing data were obtained from Gene Expression Omnibus and FerrDb databases from January 2019 to December 2023. Differentially expressed genes (DEGs) between the normal control group and the pulmonary fibrosis group were analyzed by bioinformatic method, and DEGs related to pulmonary iron addiction were extracted. The hub genes were screened by enrichment analysis, protein-protein interaction (PPI) analysis and random forest algorithm. The mouse model of pulmonary fibrosis was made for exercise intervention, and the expression of hub genes was verified by real-time quantitative reverse transcription polymerase chain reaction. Results A comparison of 103 patients with idiopathic pulmonary fibrosis and 103 normal lung tissues showed that 13 up-regulated genes and 7 down-regulated genes were identified as ferroptosis-related DEGs. PPI results showed that there was an interaction between these ferroptosis-related genes. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment and Genome Ontology enrichment analysis showed that ferroptosis-related genes were involved in organic anion transport, hypoxia response, oxygen level reduction response, hypoxia-inducible factor-1 signaling pathway, renal cell carcinoma, and arachidonic acid metabolic signaling pathway. Genes identified by PPI analysis and random forest algorithm included CAV1, NOS2, GDF15, HNF4A, and CDKN2A. Real-time fluorescence quantitative polymerase chain reaction results of mouse fibrotic lung tissue showed that compared with the exercise group, the mRNA levels of NOS2, PTGS2 and GDF15 were up-regulated and the mRNA levels of CAV1 and CDKN2A were down-regulated in the bleomycin group (P<0.05); compared with the bleomycin group, the expression of CAV1 and CDKN2A increased and the expression of NOS2, PTGS2 and GDF15 decreased in the bleomycin + exercise group (P<0.05). Conclusions Bioinformatic analysis identifies 20 potential genes associating with ferroptosis in pulmonary fibrosis. CAV1, NOS2, GDF15, and CDKN2A influence the development of pulmonary fibrosis by modulating ferroptosis. Treadmill training can reduce ferroptosis in fibrotic tissues, thereby reducing lung inflammation.

Citation： LIU Zhuo, ZHAO Zheng, ZHANG Liangliang, YANG Cuiying, JIN Zhao. Correlation analysis and mechanism study of ferroptosis with pulmonary fibrosis. West China Medical Journal, 2024, 39(8): 1238-1245. doi: 10.7507/1002-0179.202310269 Copy

1.	Strykowski R, Adegunsoye A. Idiopathic pulmonary fibrosis and progressive pulmonary fibrosis. Immunol Allergy Clin North Am, 2023, 43(2): 209-228.
2.	Amaral AF, Colares PFB, Kairalla RA. Idiopathic pulmonary fibrosis: current diagnosis and treatment. J Bras Pneumol, 2023, 49(4): e20230085.
3.	Zhao L, Zhou X, Xie F, et al. Ferroptosis in cancer and cancer immunotherapy. Cancer Commun (Lond), 2022, 42(2): 88-116.
4.	Qi J, Kim JW, Zhou Z, et al. Ferroptosis affects the progression of nonalcoholic steatohepatitis via the modulation of lipid peroxidation-mediated cell death in mice. Am J Pathol, 2020, 190(1): 68-81.
5.	Pei Z, Qin Y, Fu X, et al. Inhibition of ferroptosis and iron accumulation alleviates pulmonary fibrosis in a bleomycin model. Redox Biol, 2022, 57: 102509.
6.	Jiao Y, Huang B, Chen Y, et al. Integrated analyses reveal overexpressed notch1 promoting porcine satellite cells’ proliferation through regulating the cell cycle. Int J Mol Sci, 2018, 19(1): 271.
7.	Zhao N, Yan QW, Xia J, et al. Treadmill exercise attenuates Aβ-induced mitochondrial dysfunction and enhances mitophagy activity in APP/PS1 transgenic mice. Neurochem Res, 2020, 45(5): 1202-1214.
8.	Zheng D, Liu J, Piao H, et al. ROS-triggered endothelial cell death mechanisms: focus on pyroptosis, parthanatos, and ferroptosis. Front Immunol, 2022, 13: 1039241.
9.	Liu J, Kang R, Tang D. Signaling pathways and defense mechanisms of ferroptosis. FEBS J, 2022, 289(22): 7038-7050.
10.	Gao X, Hu W, Qian D, et al. The mechanisms of ferroptosis under hypoxia. Cell Mol Neurobiol, 2023, 43(7): 3329-3341.
11.	Erdélyi K, Ditrói T, Johansson HJ, et al. Reprogrammed transsulfuration promotes basal-like breast tumor progression via realigning cellular cysteine persulfidation. Proc Natl Acad Sci U S A, 2021, 118(45): e2100050118.
12.	Yang Y, Hong S, Lu Y, et al. CAV1 alleviated CaOx stones formation via suppressing autophagy-dependent ferroptosis. PeerJ, 2022, 10: e14033.
13.	Vaz de Paula CB, Nagashima S, Liberalesso V, et al. COVID-19: immunohistochemical analysis of TGF-β signaling pathways in pulmonary fibrosis. Int J Mol Sci, 2021, 23(1): 168.
14.	He R, Yuan X, Lv X, et al. Caveolin-1 negatively regulates inflammation and fibrosis in silicosis. J Cell Mol Med, 2022, 26(1): 99-107.
15.	Qu L, Li Y, Chen C, et al. Caveolin-1 identified as a key mediator of acute lung injury using bioinformatics and functional research. Cell Death Dis, 2022, 13(8): 686.
16.	He J, Li X. Identification and validation of aging-related genes in idiopathic pulmonary fibrosis. Front Genet, 2022, 13: 780010.
17.	Gungor H, Ekici M, Onder Karayigit M, et al. Zingerone ameliorates oxidative stress and inflammation in bleomycin-induced pulmonary fibrosis: modulation of the expression of TGF-β1 and iNOS. Naunyn Schmiedebergs Arch Pharmacol, 2020, 393(9): 1659-1670.
18.	Felix RG, Bovolato ALC, Cotrim OS, et al. Adipose-derived stem cells and adipose-derived stem cell-conditioned medium modulate in situ imbalance between collagen I- and collagen V-mediated IL-17 immune response recovering bleomycin pulmonary fibrosis. Histol Histopathol, 2020, 35(3): 289-301.
19.	Siddiqui JA, Pothuraju R, Khan P, et al. Pathophysiological role of growth differentiation factor 15 (GDF15) in obesity, cancer, and cachexia. Cytokine Growth Factor Rev, 2022, 64: 71-83.
20.	Park MR, Wong MS, Araúzo-Bravo MJ, et al. Oct4 and Hnf4α-induced hepatic stem cells ameliorate chronic liver injury in liver fibrosis model. PLoS One, 2019, 14(8): e0221085.

1. Strykowski R, Adegunsoye A. Idiopathic pulmonary fibrosis and progressive pulmonary fibrosis. Immunol Allergy Clin North Am, 2023, 43(2): 209-228.
2. Amaral AF, Colares PFB, Kairalla RA. Idiopathic pulmonary fibrosis: current diagnosis and treatment. J Bras Pneumol, 2023, 49(4): e20230085.
3. Zhao L, Zhou X, Xie F, et al. Ferroptosis in cancer and cancer immunotherapy. Cancer Commun (Lond), 2022, 42(2): 88-116.
4. Qi J, Kim JW, Zhou Z, et al. Ferroptosis affects the progression of nonalcoholic steatohepatitis via the modulation of lipid peroxidation-mediated cell death in mice. Am J Pathol, 2020, 190(1): 68-81.
5. Pei Z, Qin Y, Fu X, et al. Inhibition of ferroptosis and iron accumulation alleviates pulmonary fibrosis in a bleomycin model. Redox Biol, 2022, 57: 102509.
6. Jiao Y, Huang B, Chen Y, et al. Integrated analyses reveal overexpressed notch1 promoting porcine satellite cells’ proliferation through regulating the cell cycle. Int J Mol Sci, 2018, 19(1): 271.
7. Zhao N, Yan QW, Xia J, et al. Treadmill exercise attenuates Aβ-induced mitochondrial dysfunction and enhances mitophagy activity in APP/PS1 transgenic mice. Neurochem Res, 2020, 45(5): 1202-1214.
8. Zheng D, Liu J, Piao H, et al. ROS-triggered endothelial cell death mechanisms: focus on pyroptosis, parthanatos, and ferroptosis. Front Immunol, 2022, 13: 1039241.
9. Liu J, Kang R, Tang D. Signaling pathways and defense mechanisms of ferroptosis. FEBS J, 2022, 289(22): 7038-7050.
10. Gao X, Hu W, Qian D, et al. The mechanisms of ferroptosis under hypoxia. Cell Mol Neurobiol, 2023, 43(7): 3329-3341.
11. Erdélyi K, Ditrói T, Johansson HJ, et al. Reprogrammed transsulfuration promotes basal-like breast tumor progression via realigning cellular cysteine persulfidation. Proc Natl Acad Sci U S A, 2021, 118(45): e2100050118.
12. Yang Y, Hong S, Lu Y, et al. CAV1 alleviated CaOx stones formation via suppressing autophagy-dependent ferroptosis. PeerJ, 2022, 10: e14033.
13. Vaz de Paula CB, Nagashima S, Liberalesso V, et al. COVID-19: immunohistochemical analysis of TGF-β signaling pathways in pulmonary fibrosis. Int J Mol Sci, 2021, 23(1): 168.
14. He R, Yuan X, Lv X, et al. Caveolin-1 negatively regulates inflammation and fibrosis in silicosis. J Cell Mol Med, 2022, 26(1): 99-107.
15. Qu L, Li Y, Chen C, et al. Caveolin-1 identified as a key mediator of acute lung injury using bioinformatics and functional research. Cell Death Dis, 2022, 13(8): 686.
16. He J, Li X. Identification and validation of aging-related genes in idiopathic pulmonary fibrosis. Front Genet, 2022, 13: 780010.
17. Gungor H, Ekici M, Onder Karayigit M, et al. Zingerone ameliorates oxidative stress and inflammation in bleomycin-induced pulmonary fibrosis: modulation of the expression of TGF-β1 and iNOS. Naunyn Schmiedebergs Arch Pharmacol, 2020, 393(9): 1659-1670.
18. Felix RG, Bovolato ALC, Cotrim OS, et al. Adipose-derived stem cells and adipose-derived stem cell-conditioned medium modulate in situ imbalance between collagen I- and collagen V-mediated IL-17 immune response recovering bleomycin pulmonary fibrosis. Histol Histopathol, 2020, 35(3): 289-301.
19. Siddiqui JA, Pothuraju R, Khan P, et al. Pathophysiological role of growth differentiation factor 15 (GDF15) in obesity, cancer, and cachexia. Cytokine Growth Factor Rev, 2022, 64: 71-83.
20. Park MR, Wong MS, Araúzo-Bravo MJ, et al. Oct4 and Hnf4α-induced hepatic stem cells ameliorate chronic liver injury in liver fibrosis model. PLoS One, 2019, 14(8): e0221085.

West China Medical Journal

Correlation analysis and mechanism study of ferroptosis with pulmonary fibrosis

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