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ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

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Research Article

Identification of Drug Targets and Agents Associated with Ferroptosis-related Osteoporosis through Integrated Network Pharmacology and Molecular Docking Technology

Author(s): Kailun Huo, Yiqian Yang, Tieyi Yang, Weiwei Zhang* and Jin Shao*

Volume 30, Issue 14, 2024

Published on: 20 March, 2024

Page: [1103 - 1114] Pages: 12

DOI: 10.2174/0113816128288225240318045050

Price: $65

Abstract

Background: Osteoporosis is a systemic bone disease characterized by progressive reduction of bone mineral density and degradation of trabecular bone microstructure. Iron metabolism plays an important role in bone; its imbalance leads to abnormal lipid oxidation in cells, hence ferroptosis. In osteoporosis, however, the exact mechanism of ferroptosis has not been fully elucidated.

Objective: The main objective of this project was to identify potential drug target proteins and agents for the treatment of ferroptosis-related osteoporosis.

Methods: In the current study, we investigated the differences in gene expression of bone marrow mesenchymal stem cells between osteoporosis patients and normal individuals using bioinformatics methods to obtain ferroptosis-related genes. We could predict their protein structure based on the artificial intelligence database of AlphaFold, and their target drugs and binding sites with the network pharmacology and molecular docking technology.

Results: We identified five genes that were highly associated with osteoporosis, such as TP53, EGFR, TGFB1, SOX2 and MAPK14, which, we believe, can be taken as the potential markers and targets for the diagnosis and treatment of osteoporosis. Furthermore, we observed that these five genes were highly targeted by resveratrol to exert a therapeutic effect on ferroptosis-related osteoporosis.

Conclusion: We examined the relationship between ferroptosis and osteoporosis based on bioinformatics and network pharmacology, presenting a promising direction to the pursuit of the exact molecular mechanism of osteoporosis so that a new target can be discovered for the treatment of osteoporosis.

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[1]
Compston JE, McClung MR, Leslie WD. Osteoporosis. Lancet 2019; 393(10169): 364-76.
[http://dx.doi.org/10.1016/S0140-6736(18)32112-3] [PMID: 30696576]
[2]
Brown C. Staying strong. Nature 2017; 550(7674): S15-7.
[http://dx.doi.org/10.1038/550S15a] [PMID: 28976955]
[3]
Lane NE. Epidemiology, etiology, and diagnosis of osteoporosis. Am J Obstet Gynecol 2006; 194(S2): S3-S11.
[http://dx.doi.org/10.1016/j.ajog.2005.08.047] [PMID: 16448873]
[4]
Yang Y, Lin Y, Wang M, et al. Targeting ferroptosis suppresses osteocyte glucolipotoxicity and alleviates diabetic osteoporosis. Bone Res 2022; 10(1): 26.
[http://dx.doi.org/10.1038/s41413-022-00198-w] [PMID: 35260560]
[5]
Liu P, Wang W, Li Z, et al. Ferroptosis: A new regulatory mechanism in osteoporosis. Oxid Med Cell Longev 2022; 2022: 1-10.
[http://dx.doi.org/10.1155/2022/2634431] [PMID: 35082963]
[6]
Jiang X, Stockwell BR, Conrad M. Ferroptosis: Mechanisms, biology and role in disease. Nat Rev Mol Cell Biol 2021; 22(4): 266-82.
[http://dx.doi.org/10.1038/s41580-020-00324-8] [PMID: 33495651]
[7]
Hadian K, Stockwell BR. SnapShot: Ferroptosis. Cell 2020; 181(5): 1188-1188.e1.
[http://dx.doi.org/10.1016/j.cell.2020.04.039] [PMID: 32470402]
[8]
Chen X, Kang R, Kroemer G, Tang D. Broadening horizons: The role of ferroptosis in cancer. Nat Rev Clin Oncol 2021; 18(5): 280-96.
[http://dx.doi.org/10.1038/s41571-020-00462-0] [PMID: 33514910]
[9]
Chen X, Kang R, Kroemer G, Tang D. Ferroptosis in infection, inflammation, and immunity. J Exp Med 2021; 218(6): e20210518.
[http://dx.doi.org/10.1084/jem.20210518] [PMID: 33978684]
[10]
Li N, Jiang W, Wang W, Xiong R, Wu X, Geng Q. Ferroptosis and its emerging roles in cardiovascular diseases. Pharmacol Res 2021; 166: 105466.
[http://dx.doi.org/10.1016/j.phrs.2021.105466] [PMID: 33548489]
[11]
Xia Y, Zhang H, Wang H, et al. Identification and validation of ferroptosis key genes in bone mesenchymal stromal cells of primary osteoporosis based on bioinformatics analysis. Front Endocrinol 2022; 13: 980867.
[http://dx.doi.org/10.3389/fendo.2022.980867]
[12]
Luo C, Xu W, Tang X, et al. Canonical Wnt signaling works downstream of iron overload to prevent ferroptosis from damaging osteoblast differentiation. Free Radic Biol Med 2022; 188: 337-50.
[http://dx.doi.org/10.1016/j.freeradbiomed.2022.06.236] [PMID: 35752374]
[13]
Barrett T, Wilhite SE, Ledoux P, et al. NCBI GEO: Archive for functional genomics data sets-update. Nucleic Acids Res 2012; 41(D1): D991-5.
[http://dx.doi.org/10.1093/nar/gks1193] [PMID: 23193258]
[14]
Zhou N, Bao J. FerrDb: A manually curated resource for regulators and markers of ferroptosis and ferroptosis-disease associations. Database 2020; 2020: baaa021.
[http://dx.doi.org/10.1093/database/baaa021] [PMID: 32219413]
[15]
Szklarczyk D, Gable AL, Nastou KC, et al. The STRING database in 2021: Customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res 2021; 49(D1): D605-12.
[http://dx.doi.org/10.1093/nar/gkaa1074] [PMID: 33237311]
[16]
Shannon P, Markiel A, Ozier O, et al. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res 2003; 13(11): 2498-504.
[http://dx.doi.org/10.1101/gr.1239303] [PMID: 14597658]
[17]
Sherman BT, Hao M, Qiu J, et al. DAVID: A web server for functional enrichment analysis and functional annotation of gene lists (2021 update). Nucleic Acids Res 2022; 50(W1): W216-21.
[http://dx.doi.org/10.1093/nar/gkac194] [PMID: 35325185]
[18]
Chang L, Zhou G, Soufan O, Xia J. miRNet 2.0: Network-based visual analytics for miRNA functional analysis and systems biology. Nucleic Acids Res 2020; 48(W1): W244-51.
[http://dx.doi.org/10.1093/nar/gkaa467] [PMID: 32484539]
[19]
Yoo M, Shin J, Kim J, et al. DSigDB: Drug signatures database for gene set analysis. Bioinformatics 2015; 31(18): 3069-71.
[http://dx.doi.org/10.1093/bioinformatics/btv313] [PMID: 25990557]
[20]
Kim S, Chen J, Cheng T, et al. PubChem 2023 update. Nucleic Acids Res 2023; 51(D1): D1373-80.
[http://dx.doi.org/10.1093/nar/gkac956] [PMID: 36305812]
[21]
Jumper J, Evans R, Pritzel A, et al. Highly accurate protein structure prediction with AlphaFold. Nature 2021; 596(7873): 583-9.
[http://dx.doi.org/10.1038/s41586-021-03819-2] [PMID: 34265844]
[22]
Forli S, Huey R, Pique ME, Sanner MF, Goodsell DS, Olson AJ. Computational protein-ligand docking and virtual drug screening with the AutoDock suite. Nat Protoc 2016; 11(5): 905-19.
[http://dx.doi.org/10.1038/nprot.2016.051] [PMID: 27077332]
[23]
Eberhardt J, Santos-Martins D, Tillack AF, Forli S. AutoDock vina 1.2.0: New docking methods, expanded force field, and python bindings. J Chem Inf Model 2021; 61(8): 3891-8.
[http://dx.doi.org/10.1021/acs.jcim.1c00203] [PMID: 34278794]
[24]
Zhao N, Zhang AS, Enns CA. Iron regulation by hepcidin. J Clin Invest 2013; 123(6): 2337-43.
[http://dx.doi.org/10.1172/JCI67225] [PMID: 23722909]
[25]
Theil EC. Ferritin: The protein nanocage and iron biomineral in health and in disease. Inorg Chem 2013; 52(21): 12223-33.
[http://dx.doi.org/10.1021/ic400484n] [PMID: 24102308]
[26]
Yang WS, Stockwell BR. Ferroptosis: Death by lipid peroxidation. Trends Cell Biol 2016; 26(3): 165-76.
[http://dx.doi.org/10.1016/j.tcb.2015.10.014] [PMID: 26653790]
[27]
Yang WS, SriRamaratnam R, Welsch ME, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 2014; 156(1-2): 317-31.
[http://dx.doi.org/10.1016/j.cell.2013.12.010] [PMID: 24439385]
[28]
Ponzetti M, Rucci N. Osteoblast differentiation and signaling: Established concepts and emerging topics. Int J Mol Sci 2021; 22(13): 6651.
[http://dx.doi.org/10.3390/ijms22136651] [PMID: 34206294]
[29]
Tian Q, Qin B, Gu Y, et al. ROS-mediated necroptosis is involved in iron overload-induced osteoblastic cell death. Oxid Med Cell Longev 2020; 2020: 1-22.
[http://dx.doi.org/10.1155/2020/1295382] [PMID: 33123307]
[30]
Bai X, Lu D, Liu A, et al. Reactive oxygen species stimulates receptor activator of NF-kappaB ligand expression in osteoblast. J Biol Chem 2005; 280(17): 17497-506.
[http://dx.doi.org/10.1074/jbc.M409332200] [PMID: 15731115]
[31]
Ma J, Wang A, Zhang H, et al. Iron overload induced osteocytes apoptosis and led to bone loss in Hepcidin−/− mice through increasing sclerostin and RANKL/OPG. Bone 2022; 164: 116511.
[http://dx.doi.org/10.1016/j.bone.2022.116511] [PMID: 35933095]
[32]
Jiang L, Kon N, Li T, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature 2015; 520(7545): 57-62.
[http://dx.doi.org/10.1038/nature14344] [PMID: 25799988]
[33]
Zhen Y, Wang G, Zhu L, et al. P53 dependent mitochondrial permeability transition pore opening is required for dexamethasone-induced death of osteoblasts. J Cell Physiol 2014; 229(10): 1475-83.
[http://dx.doi.org/10.1002/jcp.24589] [PMID: 24615518]
[34]
Poursaitidis I, Wang X, Crighton T, et al. Oncogene-selective sensitivity to synchronous cell death following modulation of the amino acid nutrient cystine. Cell Rep 2017; 18(11): 2547-56.
[http://dx.doi.org/10.1016/j.celrep.2017.02.054] [PMID: 28297659]
[35]
Chandra A, Lan S, Zhu J, Siclari VA, Qin L. Epidermal growth factor receptor (EGFR) signaling promotes proliferation and survival in osteoprogenitors by increasing early growth response 2 (EGR2) expression. J Biol Chem 2013; 288(28): 20488-98.
[http://dx.doi.org/10.1074/jbc.M112.447250] [PMID: 23720781]
[36]
Kim S, Kang SW, Joo J, et al. Characterization of ferroptosis in kidney tubular cell death under diabetic conditions. Cell Death Dis 2021; 12(2): 160.
[http://dx.doi.org/10.1038/s41419-021-03452-x] [PMID: 33558472]
[37]
Kim DH, Kim WD, Kim SK, Moon DH, Lee SJ. TGF-β1-mediated repression of SLC7A11 drives vulnerability to GPX4 inhibition in hepatocellular carcinoma cells. Cell Death Dis 2020; 11(5): 406.
[http://dx.doi.org/10.1038/s41419-020-2618-6] [PMID: 32471991]
[38]
Zhang P, Zhang H, Lin J, et al. Insulin impedes osteogenesis of BMSCs by inhibiting autophagy and promoting premature senescence via the TGF-β1 pathway. Aging 2020; 12(3): 2084-100.
[http://dx.doi.org/10.18632/aging.102723] [PMID: 32017705]
[39]
Ashraf MI, Ebner M, Wallner C, et al. A p38MAPK/MK2 signaling pathway leading to redox stress, cell death and ischemia/reperfusion injury. Cell Commun Signal 2014; 12(1): 6.
[http://dx.doi.org/10.1186/1478-811X-12-6] [PMID: 24423080]
[40]
Li L, Hao Y, Zhao Y, et al. Ferroptosis is associated with oxygen-glucose deprivation/reoxygenation-induced Sertoli cell death. Int J Mol Med 2018; 41(5): 3051-62.
[http://dx.doi.org/10.3892/ijmm.2018.3469] [PMID: 29436589]
[41]
Caverzasio J, Higgins L, Ammann P. Prevention of trabecular bone loss induced by estrogen deficiency by a selective p38alpha inhibitor. J Bone Miner Res 2008; 23(9): 1389-97.
[http://dx.doi.org/10.1359/jbmr.080410] [PMID: 18442314]
[42]
Wang X, Chen Y, Wang X, et al. Stem cell factor SOX2 confers ferroptosis resistance in lung cancer via upregulation of SLC7A11. Cancer Res 2021; 81(20): 5217-29.
[http://dx.doi.org/10.1158/0008-5472.CAN-21-0567] [PMID: 34385181]
[43]
Gan L, Leng Y, Min J, Luo XM, Wang F, Zhao J. Kaempferol promotes the osteogenesis in rBMSCs via mediation of SOX2/miR-124-3p/PI3K/Akt/mTOR axis. Eur J Pharmacol 2022; 927: 174954.
[http://dx.doi.org/10.1016/j.ejphar.2022.174954] [PMID: 35421359]
[44]
Lu X, Kang N, Ling X, Pan M, Du W, Gao S. MiR-27a-3p promotes non-small cell lung cancer through SLC7A11-mediated-ferroptosis. Front Oncol 2021; 11: 759346.
[http://dx.doi.org/10.3389/fonc.2021.759346] [PMID: 34722314]
[45]
Ren LR, Yao RB, Wang SY, Gong XD, Xu JT, Yang KS. MiR-27a-3p promotes the osteogenic differentiation by activating CRY2/ERK1/2 axis. Mol Med 2021; 27(1): 43.
[http://dx.doi.org/10.1186/s10020-021-00303-5] [PMID: 33902432]
[46]
Chen X, Song X, Zhao X, et al. Insights into the anti-inflammatory and antiviral mechanisms of resveratrol. Mediators Inflamm 2022; 2022: 1-11.
[http://dx.doi.org/10.1155/2022/7138756] [PMID: 35990040]
[47]
Liu J, Zhang M, Qin C, et al. Resveratrol attenuate myocardial injury by inhibiting ferroptosis via inducing KAT5/GPX4 in myocardial infarction. Front Pharmacol 2022; 13: 906073.
[http://dx.doi.org/10.3389/fphar.2022.906073] [PMID: 35685642]
[48]
Pearson KJ, Baur JA, Lewis KN, et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 2008; 8(2): 157-68.
[http://dx.doi.org/10.1016/j.cmet.2008.06.011] [PMID: 18599363]
[49]
Xiu X, Puskar NL, Shanata JAP, Lester HA, Dougherty DA. Nicotine binding to brain receptors requires a strong cation-π interaction. Nature 2009; 458(7237): 534-7.
[http://dx.doi.org/10.1038/nature07768] [PMID: 19252481]
[50]
Zhu T, Shi L, Yu C, et al. Ferroptosis promotes photodynamic therapy: Supramolecular photosensitizer-inducer nanodrug for enhanced cancer treatment. Theranostics 2019; 9(11): 3293-307.
[http://dx.doi.org/10.7150/thno.32867] [PMID: 31244955]
[51]
Das S, Lin HS, Ho PC, Ng KY. The impact of aqueous solubility and dose on the pharmacokinetic profiles of resveratrol. Pharm Res 2008; 25(11): 2593-600.
[http://dx.doi.org/10.1007/s11095-008-9677-1] [PMID: 18629618]
[52]
Kosuru R, Rai U, Prakash S, Singh A, Singh S. Promising therapeutic potential of pterostilbene and its mechanistic insight based on preclinical evidence. Eur J Pharmacol 2016; 789: 229-43.
[http://dx.doi.org/10.1016/j.ejphar.2016.07.046] [PMID: 27475678]
[53]
Lin HS, Yue BD, Ho PC. Determination of pterostilbene in rat plasma by a simple HPLC-UV method and its application in pre- clinical pharmacokinetic study. Biomed Chromatogr 2009; 23(12): 1308-15.
[http://dx.doi.org/10.1002/bmc.1254] [PMID: 19488981]
[54]
Larrosa M, Barberán TFA, Espín JC. The grape and wine polyphenol piceatannol is a potent inducer of apoptosis in human SK-Mel-28 melanoma cells. Eur J Nutr 2004; 43(5): 275-84.
[http://dx.doi.org/10.1007/s00394-004-0471-5] [PMID: 15309446]
[55]
Chen W, Yeo SCM, Elhennawy MGAA, Xiang X, Lin HS. Determination of naturally occurring resveratrol analog trans-4,4′-dihydroxystilbene in rat plasma by liquid chromatography-tandem mass spectrometry: Application to a pharmacokinetic study. Anal Bioanal Chem 2015; 407(19): 5793-801.
[http://dx.doi.org/10.1007/s00216-015-8762-7] [PMID: 25998136]
[56]
Li XZ, Wei X, Zhang CJ, et al. Hypohalous acid-mediated halogenation of resveratrol and its role in antioxidant and antimicrobial activities. Food Chem 2012; 135(3): 1239-44.
[http://dx.doi.org/10.1016/j.foodchem.2012.05.043] [PMID: 22953849]
[57]
Lee EJ, Min HY, Joo Park H, et al. G2/M cell cycle arrest and induction of apoptosis by a stilbenoid, 3,4,5-trimethoxy-4′-bromo- cis-stilbene, in human lung cancer cells. Life Sci 2004; 75(23): 2829-39.
[http://dx.doi.org/10.1016/j.lfs.2004.07.002] [PMID: 15464834]

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