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Cited by 199Ferroptosis and cancer prognosisGenomics, phytochemicals, and oxidative stressIron Metabolism and Disorders

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Nrf2 attenuates ferroptosis-mediated IIR-ALI by modulating TERT and SLC7A11

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Dong, Hui, Xia, Yangyang, Jin, Shanliang, Xue, Chaofan, Wang, Yanjun, Hu, Rong, Jiang, Hong·2021·Cell Death & Disease
DOI 10.1038/s41419-021-04307-1PMC PMC8556385
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Abstract

Acute lung injury (ALI) carries a mortality rate of ~50% and is a hot topic in the world of critical illness research. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical modulator of intracellular oxidative homeostasis and serves as an antioxidant. The Nrf2-related anti-oxidative stress is strongly associated with ferroptosis suppression. Meanwhile, telomerase reverse transcriptase (TERT), the catalytic portion of the telomerase protein, is reported to travel to the mitochondria to alleviate ROS. In our study, we found that TERT was significantly reduced in lung tissue of Nrf2 −/− mice in the model of intestinal ischemia/reperfusion-induced acute lung injury (IIR-ALI). In addition, MDA levels showed marked increase, whereas GSH and GPX4 levels fell drastically in ALI models. Moreover, typical-related structural changes were observed in the type II alveolar epithelial cells in the IIR model. We further employed the scanning transmission X-ray microscopy (STXM) to examine Fe levels and distribution within cells. Based on our observations, massive aggregates of Fe were found in the MLE-12 cells upon OGD/R (oxygen and glucose deprivation/reperfusion) induction. Additionally, Nrf2 silencing dramatically reduced TERT and SLC7A11 levels, and further exacerbated cellular injuries. In contrast, TERT-overexpressing cells exhibited marked elevation in SLC7A11 levels and thereby inhibited ferroptosis. Collectively, these data suggest that Nrf2 can negatively regulate ferroptosis via modulation of TERT and SLC7A11 levels. The conclusion from this study brings insight into new candidates that can be targeted in future IIR-ALI therapy.

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Fig. 1 II/R-induced ALI promotes ferroptosis. A Endogenous Fe levels in the lungs of IIR-ALI mice, as evidenced by Fe assay. B Representative transmission electron micrographs of lung ultrastructure. Scale bars: 500 nm. C, D Evaluation and quantification of the GPX4, ferritin, and ferroportin protein expressions, under all conditions. E Evaluation of the lipid peroxide MDA levels under all conditions. F GSH levels under all conditions. G HE staining of the murine lung tissues after IIR and IIR + Fer-1. Scale bars: 200 μm. H The lung pathological damage score illustrating addition and decrease after Fer-1 administration, respectively. Data are expressed as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. Error bars denote standard error from three individual experiments.
Fig. 1 II/R-induced ALI promotes ferroptosis. A Endogenous Fe levels in the lungs of IIR-ALI mice, as evidenced by Fe assay. B Representative transmission electron micrographs of lung ultrastructure. Scale bars: 500 nm. C, D Evaluation and quantification of the GPX4, ferritin, and ferroportin protein expressions, under all conditions. E Evaluation of the lipid peroxide MDA levels under all conditions. F GSH levels under all conditions. G HE staining of the murine lung tissues after IIR and IIR + Fer-1. Scale bars: 200 μm. H The lung pathological damage score illustrating addition and decrease after Fer-1 administration, respectively. Data are expressed as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. Error bars denote standard error from three individual experiments.CC BY · PubMed Central
Fig. 2 The Nrf2/TERT/SLC7A11 axis is activated during II/R and the ferroptotic process is dysregulated in the Nrf2−/− mice after II/R. A Evaluation of Nrf2 and its potential downstream targets in the murine lung tissues, under different conditions, as evidenced by western blotting. B Quantification of the examined proteins. C mRNA levels of the examined factors. D Representative transmission electron micrographs of the lung tissue ultrastructures. Scale bar: 500 nm. E HE staining of lung sections, observed under a light microscope. Scale bar: 200 μm. F Pathological scores, as determined by an experienced pathologist. G MDA levels under different conditions. H GSH levels under different conditions. I Evaluation of essential proteins involved in ferroptosis regulation within lung tissues, under different conditions. J Quantification of the examined proteins. K mRNA levels of the examined factors. Error bars denote standard error from three individual experiments. Data are expressed as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. # relative to the IIR-WT mice.
Fig. 2 The Nrf2/TERT/SLC7A11 axis is activated during II/R and the ferroptotic process is dysregulated in the Nrf2−/− mice after II/R. A Evaluation of Nrf2 and its potential downstream targets in the murine lung tissues, under different conditions, as evidenced by western blotting. B Quantification of the examined proteins. C mRNA levels of the examined factors. D Representative transmission electron micrographs of the lung tissue ultrastructures. Scale bar: 500 nm. E HE staining of lung sections, observed under a light microscope. Scale bar: 200 μm. F Pathological scores, as determined by an experienced pathologist. G MDA levels under different conditions. H GSH levels under different conditions. I Evaluation of essential proteins involved in ferroptosis regulation within lung tissues, under different conditions. J Quantification of the examined proteins. K mRNA levels of the examined factors. Error bars denote standard error from three individual experiments. Data are expressed as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. # relative to the IIR-WT mice.CC BY · PubMed Central
Fig. 3 OGD/R accelerates ferroptosis within pulmonary epithelial cells and enhances Nrf2, TERT, and SLC7A11 levels during ferroptosis. A Fe L3-edge NEXAFS (near edge X-ray absorption fine structure) spectrum was acquired from two absorption cellular images scanned at two energies, E1 (709 eV) and E2 (705 eV) above and below the absorption edge of Fe, respectively. B Evaluation of Fe distribution and content using scanning transmission X-ray microscopy. C Endogenous Fe levels within the pulmonary epithelial cells of the OGD/R model, as detected by Fe assay. D Evaluation of the levels of ferroptosis-related proteins under different conditions. E Quantification of the examined proteins. F Evaluation of ferritin and ferroportin levels (red) in lung tissues, using immunohistochemistry. Nuclear staining done with DAPI (blue) after OGD/R. Scale bar: 100 μm. G Cell survival after OGD/R induction and the opposite effect with Fer-1 (0.1 μM). H GSH levels under different conditions. I MDA levels under different conditions. Error bars denote standard error from three individual experiments. Data are expressed as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; *relative to control; #relative to OGD/R.
Fig. 3 OGD/R accelerates ferroptosis within pulmonary epithelial cells and enhances Nrf2, TERT, and SLC7A11 levels during ferroptosis. A Fe L3-edge NEXAFS (near edge X-ray absorption fine structure) spectrum was acquired from two absorption cellular images scanned at two energies, E1 (709 eV) and E2 (705 eV) above and below the absorption edge of Fe, respectively. B Evaluation of Fe distribution and content using scanning transmission X-ray microscopy. C Endogenous Fe levels within the pulmonary epithelial cells of the OGD/R model, as detected by Fe assay. D Evaluation of the levels of ferroptosis-related proteins under different conditions. E Quantification of the examined proteins. F Evaluation of ferritin and ferroportin levels (red) in lung tissues, using immunohistochemistry. Nuclear staining done with DAPI (blue) after OGD/R. Scale bar: 100 μm. G Cell survival after OGD/R induction and the opposite effect with Fer-1 (0.1 μM). H GSH levels under different conditions. I MDA levels under different conditions. Error bars denote standard error from three individual experiments. Data are expressed as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; *relative to control; #relative to OGD/R.CC BY · PubMed Central
Fig. 4 Nrf2 stimulation prevents ferroptosis and the absence of Nrf2 produces more serious ferroptosis phenotype in OGD/R. A Evaluation of Nrf2 and its potential downstream proteins via western blotting, under different conditions. B Quantification of the examined proteins. C Fe distribution and content detected via scanning transmission X-ray microscopy. D, M Evaluation of cell viability after OGD/R induction, as evidenced by CCK8 assay. Cells were assigned to three categories: (1) control, (2) OGD/R, and (3) OGD/R + Fer-1 (0.1 μM). E, N Endogenous Fe levels within pulmonary epithelial cells in the OGD/R model, as detected by Fe assay. F, O MDA levels after OGD/R induction, as assessed by MDA assay. G, P GSH levels after OGD/R induction, as assessed by GSH assay. H, Q Evaluation of ferritin and ferroportin (red), using immunohistochemistry. Nuclear staining done with DAPI (blue) after OGD/R induction. Scale bar: 100 μm. I–L, R–U Evaluation and quantification of ferroportin and GPX4 protein levels. Error bars denote standard error from three individual experiments. Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 represent intergroup significant differences. *Relative to the sham control mice. #Relative to the OGD/R control.
Fig. 4 Nrf2 stimulation prevents ferroptosis and the absence of Nrf2 produces more serious ferroptosis phenotype in OGD/R. A Evaluation of Nrf2 and its potential downstream proteins via western blotting, under different conditions. B Quantification of the examined proteins. C Fe distribution and content detected via scanning transmission X-ray microscopy. D, M Evaluation of cell viability after OGD/R induction, as evidenced by CCK8 assay. Cells were assigned to three categories: (1) control, (2) OGD/R, and (3) OGD/R + Fer-1 (0.1 μM). E, N Endogenous Fe levels within pulmonary epithelial cells in the OGD/R model, as detected by Fe assay. F, O MDA levels after OGD/R induction, as assessed by MDA assay. G, P GSH levels after OGD/R induction, as assessed by GSH assay. H, Q Evaluation of ferritin and ferroportin (red), using immunohistochemistry. Nuclear staining done with DAPI (blue) after OGD/R induction. Scale bar: 100 μm. I–L, R–U Evaluation and quantification of ferroportin and GPX4 protein levels. Error bars denote standard error from three individual experiments. Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 represent intergroup significant differences. *Relative to the sham control mice. #Relative to the OGD/R control.CC BY · PubMed Central
Fig. 5 Nrf2 positively regulates TERT and SLC7A11 levels during OGD/R-driven ferroptosis in pulmonary epithelial cells. A, E Evaluation of Nrf2 and its potential downstream signaling proteins via western blotting, under different conditions. B–D, F–H Quantification of the examined proteins. Error bars denote standard error from three individual experiments. Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 represent intergroup significant differences.
Fig. 5 Nrf2 positively regulates TERT and SLC7A11 levels during OGD/R-driven ferroptosis in pulmonary epithelial cells. A, E Evaluation of Nrf2 and its potential downstream signaling proteins via western blotting, under different conditions. B–D, F–H Quantification of the examined proteins. Error bars denote standard error from three individual experiments. Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 represent intergroup significant differences.CC BY · PubMed Central
Fig. 6 Low TERT levels enhance ferroptosis, whereas TERT overexpression (OETERT) alleviates ferroptosis via upregulating SLC7A11. A Fe distribution and content. B, I Evaluation of cell viability after OGD/R, as evidenced by CCK8 assay. C, J MDA levels after OGD/R, as assessed by MDA assay. D, K GSH levels after OGD/R, as assessed by GSH assay. E, L Evaluation of ferritin and ferroportin (red), using immunohistochemistry. Nuclear staining done with DAPI (blue) after OGD/R. Scale bar: 100 μm. F, M Evaluation of Nrf2 and its potential downstream proteins via western blotting under different treatment conditions. G, N Protein quantification. H, O mRNA levels of the examined factors. Error bars denote standard error from three individual experiments. Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 denotes intergroup significant difference. *Relative to the sham control mice. #Relative to the OGD/R controls.
Fig. 6 Low TERT levels enhance ferroptosis, whereas TERT overexpression (OETERT) alleviates ferroptosis via upregulating SLC7A11. A Fe distribution and content. B, I Evaluation of cell viability after OGD/R, as evidenced by CCK8 assay. C, J MDA levels after OGD/R, as assessed by MDA assay. D, K GSH levels after OGD/R, as assessed by GSH assay. E, L Evaluation of ferritin and ferroportin (red), using immunohistochemistry. Nuclear staining done with DAPI (blue) after OGD/R. Scale bar: 100 μm. F, M Evaluation of Nrf2 and its potential downstream proteins via western blotting under different treatment conditions. G, N Protein quantification. H, O mRNA levels of the examined factors. Error bars denote standard error from three individual experiments. Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 denotes intergroup significant difference. *Relative to the sham control mice. #Relative to the OGD/R controls.CC BY · PubMed Central
Fig. 7 TERT inhibited ferroptosis-dependent OGD/R injury by facilitated SLC7A11 expression in vitro. A, D GSH levels after OGD/R, as assessed by GSH assay. B, E MDA levels after OGD/R, as assessed by MDA assay. C, F Endogenous Fe levels within pulmonary epithelial cells in the OGD/R model, as detected by Fe assay. G, K Evaluation of TERT, SLC7A11, and GPX4 protein expression via western blotting under different treatment conditions. H–J, L–N Protein quantification. Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 denotes intergroup significant difference.
Fig. 7 TERT inhibited ferroptosis-dependent OGD/R injury by facilitated SLC7A11 expression in vitro. A, D GSH levels after OGD/R, as assessed by GSH assay. B, E MDA levels after OGD/R, as assessed by MDA assay. C, F Endogenous Fe levels within pulmonary epithelial cells in the OGD/R model, as detected by Fe assay. G, K Evaluation of TERT, SLC7A11, and GPX4 protein expression via western blotting under different treatment conditions. H–J, L–N Protein quantification. Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 denotes intergroup significant difference.CC BY · PubMed Central

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Metadata

Authors
Dong, H., Xia, Y., Jin, S., Xue, C., Wang, Y., Hu, R., & Jiang, H.
Affiliations
  • Shanghai Jiao Tong University (CN)
  • Chinese Academy of Sciences (CN)
Corresponding author
  • Hu, Rong
  • Jiang, Hong
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2021-10-29
Volume
12
Issue
11
Pages
1027-1027
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/s41419-021-04307-1
PMC
PMC8556385
OpenAlex
W3209906264
Cited by
196
References
35
Citations by year
2026: 29 · 2025: 40 · 2024: 65 · 2023: 36 · 2022: 26
FWCI
21.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Science and Technology Commission of Shanghai Municipality (19ZR1476500)
  • National Natural Science Foundation of China (81970065)
  • Youth Innovation Promotion Association of the Chinese Academy of Sciences (2017306)
  • the Incentive Project of High-level Innovation Team for Shanghai Jiao Tong University School of Medicine
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
Keywords
Nrf2, ferroptosis, telomerase reverse transcriptase, SLC7A11, telomerase, oxidative stress, iron accumulation, GPX4, glutathione, alveolar epithelial cells, Nrf2 knockout mice
MeSH terms
Ferroptosis, Animals, Cell Line, Transformed, Disease Models, Animal, Glucose, Intestines, Iron, Mice, Inbred C57BL, Oxygen, Signal Transduction, Reperfusion Injury, Mice, Knockout, Telomerase, Gene Silencing, Amino Acid Transport System y+, NF-E2-Related Factor 2, Mice, Acute Lung Injury, Alveolar Epithelial Cells

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