Activating transcription factor 3 may be a biomarker of ferroptosis in lupus nephritis: a study based on bioinformatics analysis_West China Medical Journal

Authors：

ZHANG Dongmei ^1,2 , JIANG Zheng ^1,2 , ZHANG Liling ^1,2 ,  ZHU Tingting ^1,2

1. Department of Nephrology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P. R. China;
2. Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan 646000, P. R. China;

Corresponding author：

ZHU Tingting, Email: 455079204@qq.com

Keywords：

Lupus nephritis; ferroptosis; activating transcription factor 3; bioinformatics analysis; competing endogenous RNA

DOI：

10.7507/1002-0179.202305094

Video：

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Objective A series of bioinformatics methods were used to identify ferroptosis related biomarkers in lupus nephritis (LN). Methods We retrieved sequencing data of GSE112943 from the GEO (Gene Expression Omnibus) database and screened LN differentially expressed genes. We searched for ferroptosis-related gene (FRG) through FerrDb database, and screened LN-FRG. We conducted enrichment analysis on the LN-FRGs using David online bioinformatics database and screened the core LN-FRG using cytoHubba. We used external data sets to verify the core LN-FRGs, constructed competing endogenous RNA networks, and conducted molecular docking analysis. Results A total of 37 LN-FRGs were selected through screening. These genes are mainly enriched in inflammation, immune regulation and ferroptosis related signaling pathways. Through the cytoHubba and external dataset validation, the key core LN-FRG of ATF3 (activating transcription factor 3) was ultimately identified, and its expression was significantly increased in LN (P<0.05). Molecular docking analysis showed that ATF3 was closely bound to SLC7A11 and NRF2, and may participate in the occurrence and development of LN through the microRNA-27-ATF3 regulation axis. Conclusion The pivotal gene ATF3 may participate in the inflammation and immune injury of LN through ferroptosis.

Citation： ZHANG Dongmei, JIANG Zheng, ZHANG Liling, ZHU Tingting. Activating transcription factor 3 may be a biomarker of ferroptosis in lupus nephritis: a study based on bioinformatics analysis. West China Medical Journal, 2023, 38(7): 1006-1013. doi: 10.7507/1002-0179.202305094 Copy

1.	Furie RA, Aroca G, Cascino MD, et al. B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis, 2022, 81(1): 100-107.
2.	Yu C, Li P, Dang X, et al. Lupus nephritis: new progress in diagnosis and treatment. J Autoimmun, 2022, 132: 102871.
3.	Chen X, Kang R, Kroemer G, et al. Ferroptosis in infection, inflammation, and immunity. J Exp Med, 2021, 218(6): e20210518.
4.	Mou Y, Wang J, Wu J, et al. Ferroptosis, a new form of cell death: opportunities and challenges in cancer. J Hematol Oncol, 2019, 12(1): 34.
5.	Marks ES, Bonnemaison ML, Brusnahan SK, et al. Renal iron accumulation occurs in lupus nephritis and iron chelation delays the onset of albuminuria. Sci Rep, 2017, 7(1): 12821.
6.	Wang Z, Yin W, Zhu L, et al. Iron drives T helper cell pathogenicity by promoting RNA-binding protein PCBP1-mediated proinflammatory cytokine production. Immunity, 2018, 49(1): 80-92. e7.
7.	Wang W, Lin Z, Feng J, et al. Identification of ferroptosis-related molecular markers in glomeruli and tubulointerstitium of lupus nephritis. Lupus, 2022, 31(8): 985-997.
8.	Scindia Y, Wlazlo E, Ghias E, et al. Modulation of iron homeostasis with hepcidin ameliorates spontaneous murine lupus nephritis. Kidney Int, 2020, 98(1): 100-115.
9.	Lee J, Roh JL. SLC7A11 as a gateway of metabolic perturbation and ferroptosis vulnerability in cancer. Antioxidants (Basel), 2022, 11(12): 2444.
10.	Dodson M, Castro-Portuguez R, Zhang DD. NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol, 2019, 23: 101107.
11.	Liu P, Lu Z, Liu L, et al. NOD-like receptor signaling in inflammation-associated cancers: from functions to targeted therapies. Phytomedicine, 2019, 64: 152925.
12.	Chen T, Zhang X, Zhu G, et al. Quercetin inhibits TNF-α induced HUVECs apoptosis and inflammation via downregulating NF-kB and AP-1 signaling pathway in vitro. Medicine (Baltimore), 2020, 99(38): e22241.
13.	Li ST, Dai Q, Zhang SX, et al. Ulinastatin attenuates LPS-induced inflammation in mouse macrophage RAW264.7 cells by inhibiting the JNK/NF-κB signaling pathway and activating the PI3K/Akt/Nrf2 pathway. Acta Pharmacol Sin, 2018, 39(8): 1294-1304.
14.	Fitzgerald KA, Kagan JC. Toll-like receptors and the control of immunity. Cell, 2020, 180(6): 1044-1066.
15.	Lu S, Song Y, Luo R, et al. Ferroportin-dependent iron homeostasis protects against oxidative stress-induced nucleus pulposus cell ferroptosis and ameliorates intervertebral disc degeneration in vivo. Oxid Med Cell Longev, 2021, 2021: 6670497.
16.	Wu D, Ai L, Sun Y, et al. Role of NLRP3 inflammasome in lupus nephritis and therapeutic targeting by phytochemicals. Front Pharmacol, 2021, 12: 621300.
17.	Zhao M, Li MY, Gao XF, et al. Downregulation of BDH2 modulates iron homeostasis and promotes DNA demethylation in CD4⁺ T cells of systemic lupus erythematosus. Clin Immunol, 2018, 187: 113-121.
18.	Piattini F, Matsushita M, Muri J, et al. Differential sensitivity of inflammatory macrophages and alternatively activated macrophages to ferroptosis. Eur J Immunol, 2021, 51(10): 2417-2429.
19.	Kapralov AA, Yang Q, Dar HH, et al. Redox lipid reprogramming commands susceptibility of macrophages and microglia to ferroptotic death. Nat Chem Biol, 2020, 16(3): 278-290.
20.	Li P, Jiang M, Li K, et al. Glutathione peroxidase 4-regulated neutrophil ferroptosis induces systemic autoimmunity. Nat Immunol, 2021, 22(9): 1107-1117.
21.	Liang G, Wolfgang CD, Chen BP, et al. ATF3 gene. Genomic organization, promoter, and regulation. J Biol Chem, 1996, 271(3): 1695-701.
22.	Liu H, Mo H, Yang C, et al. A novel function of ATF3 in suppression of ferroptosis in mouse heart suffered ischemia/reperfusion. Free Radic Biol Med, 2022, 189: 122-135.
23.	Lu S, Wang XZ, He C, et al. ATF3 contributes to brucine-triggered glioma cell ferroptosis via promotion of hydrogen peroxide and iron. Acta Pharmacol Sin, 2021, 42(10): 1690-1702.
24.	Li Y, Yan J, Zhao Q, et al. ATF3 promotes ferroptosis in sorafenib-induced cardiotoxicity by suppressing Slc7a11 expression. Front Pharmacol, 2022, 13: 904314.
25.	Zhao Y, Du Y, Gao Y, et al. ATF3 regulates osteogenic function by mediating osteoblast ferroptosis in type 2 diabetic osteoporosis. Dis Markers, 2022, 2022: 9872243.
26.	Wang Y, Chen D, Xie H, et al. AUF1 protects against ferroptosis to alleviate sepsis-induced acute lung injury by regulating NRF2 and ATF3. Cell Mol Life Sci, 2022, 79(5): 228.
27.	Wu X, Qiu F, Jin X, et al. ATF3: a novel biomarker for the diagnosis of acute kidney injury after cardiac surgery. Ann Transl Med, 2021, 9(22): 1655.
28.	Zhou H, Cheruvanky A, Hu X, et al. Urinary exosomal transcription factors, a new class of biomarkers for renal disease. Kidney Int, 2008, 74(5): 613-621.
29.	Li G, Zhang J, Liu D, et al. Identification of hub genes and potential ceRNA networks of diabetic nephropathy by weighted gene co-expression network analysis. Front Genet, 2021, 12: 767654.
30.	Zhu B, Ni Y, Gong Y, et al. Formononetin ameliorates ferroptosis-associated fibrosis in renal tubular epithelial cells and in mice with chronic kidney disease by suppressing the Smad3/ATF3/SLC7A11 signaling. Life Sci, 2023, 315: 121331.
31.	Yang Q, Zhang D, Li Y, et al. Paclitaxel alleviated liver injury of septic mice by alleviating inflammatory response via microRNA-27a/TAB3/NF-κB signaling pathway. Biomed Pharmacother, 2018, 97: 1424-1433.
32.	Guo D, Li Q, Lv Q, et al. MiR-27a targets sFRP1 in hFOB cells to regulate proliferation, apoptosis and differentiation. PLoS One, 2014, 9(3): e91354.
33.	Lei S, Chen G, Deng L, et al. Upregulation of miR-27b facilitates apoptosis of TNF-α-stimulated fibroblast-like synoviocytes. Yonsei Med J, 2019, 60(6): 585-591.

1. Furie RA, Aroca G, Cascino MD, et al. B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis, 2022, 81(1): 100-107.
2. Yu C, Li P, Dang X, et al. Lupus nephritis: new progress in diagnosis and treatment. J Autoimmun, 2022, 132: 102871.
3. Chen X, Kang R, Kroemer G, et al. Ferroptosis in infection, inflammation, and immunity. J Exp Med, 2021, 218(6): e20210518.
4. Mou Y, Wang J, Wu J, et al. Ferroptosis, a new form of cell death: opportunities and challenges in cancer. J Hematol Oncol, 2019, 12(1): 34.
5. Marks ES, Bonnemaison ML, Brusnahan SK, et al. Renal iron accumulation occurs in lupus nephritis and iron chelation delays the onset of albuminuria. Sci Rep, 2017, 7(1): 12821.
6. Wang Z, Yin W, Zhu L, et al. Iron drives T helper cell pathogenicity by promoting RNA-binding protein PCBP1-mediated proinflammatory cytokine production. Immunity, 2018, 49(1): 80-92. e7.
7. Wang W, Lin Z, Feng J, et al. Identification of ferroptosis-related molecular markers in glomeruli and tubulointerstitium of lupus nephritis. Lupus, 2022, 31(8): 985-997.
8. Scindia Y, Wlazlo E, Ghias E, et al. Modulation of iron homeostasis with hepcidin ameliorates spontaneous murine lupus nephritis. Kidney Int, 2020, 98(1): 100-115.
9. Lee J, Roh JL. SLC7A11 as a gateway of metabolic perturbation and ferroptosis vulnerability in cancer. Antioxidants (Basel), 2022, 11(12): 2444.
10. Dodson M, Castro-Portuguez R, Zhang DD. NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol, 2019, 23: 101107.
11. Liu P, Lu Z, Liu L, et al. NOD-like receptor signaling in inflammation-associated cancers: from functions to targeted therapies. Phytomedicine, 2019, 64: 152925.
12. Chen T, Zhang X, Zhu G, et al. Quercetin inhibits TNF-α induced HUVECs apoptosis and inflammation via downregulating NF-kB and AP-1 signaling pathway in vitro. Medicine (Baltimore), 2020, 99(38): e22241.
13. Li ST, Dai Q, Zhang SX, et al. Ulinastatin attenuates LPS-induced inflammation in mouse macrophage RAW264.7 cells by inhibiting the JNK/NF-κB signaling pathway and activating the PI3K/Akt/Nrf2 pathway. Acta Pharmacol Sin, 2018, 39(8): 1294-1304.
14. Fitzgerald KA, Kagan JC. Toll-like receptors and the control of immunity. Cell, 2020, 180(6): 1044-1066.
15. Lu S, Song Y, Luo R, et al. Ferroportin-dependent iron homeostasis protects against oxidative stress-induced nucleus pulposus cell ferroptosis and ameliorates intervertebral disc degeneration in vivo. Oxid Med Cell Longev, 2021, 2021: 6670497.
16. Wu D, Ai L, Sun Y, et al. Role of NLRP3 inflammasome in lupus nephritis and therapeutic targeting by phytochemicals. Front Pharmacol, 2021, 12: 621300.
17. Zhao M, Li MY, Gao XF, et al. Downregulation of BDH2 modulates iron homeostasis and promotes DNA demethylation in CD4⁺ T cells of systemic lupus erythematosus. Clin Immunol, 2018, 187: 113-121.
18. Piattini F, Matsushita M, Muri J, et al. Differential sensitivity of inflammatory macrophages and alternatively activated macrophages to ferroptosis. Eur J Immunol, 2021, 51(10): 2417-2429.
19. Kapralov AA, Yang Q, Dar HH, et al. Redox lipid reprogramming commands susceptibility of macrophages and microglia to ferroptotic death. Nat Chem Biol, 2020, 16(3): 278-290.
20. Li P, Jiang M, Li K, et al. Glutathione peroxidase 4-regulated neutrophil ferroptosis induces systemic autoimmunity. Nat Immunol, 2021, 22(9): 1107-1117.
21. Liang G, Wolfgang CD, Chen BP, et al. ATF3 gene. Genomic organization, promoter, and regulation. J Biol Chem, 1996, 271(3): 1695-701.
22. Liu H, Mo H, Yang C, et al. A novel function of ATF3 in suppression of ferroptosis in mouse heart suffered ischemia/reperfusion. Free Radic Biol Med, 2022, 189: 122-135.
23. Lu S, Wang XZ, He C, et al. ATF3 contributes to brucine-triggered glioma cell ferroptosis via promotion of hydrogen peroxide and iron. Acta Pharmacol Sin, 2021, 42(10): 1690-1702.
24. Li Y, Yan J, Zhao Q, et al. ATF3 promotes ferroptosis in sorafenib-induced cardiotoxicity by suppressing Slc7a11 expression. Front Pharmacol, 2022, 13: 904314.
25. Zhao Y, Du Y, Gao Y, et al. ATF3 regulates osteogenic function by mediating osteoblast ferroptosis in type 2 diabetic osteoporosis. Dis Markers, 2022, 2022: 9872243.
26. Wang Y, Chen D, Xie H, et al. AUF1 protects against ferroptosis to alleviate sepsis-induced acute lung injury by regulating NRF2 and ATF3. Cell Mol Life Sci, 2022, 79(5): 228.
27. Wu X, Qiu F, Jin X, et al. ATF3: a novel biomarker for the diagnosis of acute kidney injury after cardiac surgery. Ann Transl Med, 2021, 9(22): 1655.
28. Zhou H, Cheruvanky A, Hu X, et al. Urinary exosomal transcription factors, a new class of biomarkers for renal disease. Kidney Int, 2008, 74(5): 613-621.
29. Li G, Zhang J, Liu D, et al. Identification of hub genes and potential ceRNA networks of diabetic nephropathy by weighted gene co-expression network analysis. Front Genet, 2021, 12: 767654.
30. Zhu B, Ni Y, Gong Y, et al. Formononetin ameliorates ferroptosis-associated fibrosis in renal tubular epithelial cells and in mice with chronic kidney disease by suppressing the Smad3/ATF3/SLC7A11 signaling. Life Sci, 2023, 315: 121331.
31. Yang Q, Zhang D, Li Y, et al. Paclitaxel alleviated liver injury of septic mice by alleviating inflammatory response via microRNA-27a/TAB3/NF-κB signaling pathway. Biomed Pharmacother, 2018, 97: 1424-1433.
32. Guo D, Li Q, Lv Q, et al. MiR-27a targets sFRP1 in hFOB cells to regulate proliferation, apoptosis and differentiation. PLoS One, 2014, 9(3): e91354.
33. Lei S, Chen G, Deng L, et al. Upregulation of miR-27b facilitates apoptosis of TNF-α-stimulated fibroblast-like synoviocytes. Yonsei Med J, 2019, 60(6): 585-591.

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