Unraveling the Anemia Nexus: Bioinformatics-Driven Discovery of Key Protein Interactions and Therapeutic Targets
,
Abstract
Anemia, characterized by a deficiency in red blood cells or their oxygen-carrying capacity, is a prevalent condition with significant health impacts. This study utilizes a bioinformatics approach to identify key proteins involved in anemia, leveraging multiple centrality metrics within the anemia protein interaction network to uncover potential therapeutic targets. By analyzing genomic and proteomic data, we identified critical proteins using centrality metrics, including Degree, Closeness, Betweenness, and Radiality. The study focused on five key proteins: GAPDH, EEF2, TPI1, ACO1, and RPS13. These proteins were assessed for their roles in cellular processes related to anemia. Our findings highlight GAPDH's multifunctional roles in glycolysis and iron homeostasis, EEF2's regulation of protein synthesis under stress, TPI1's crucial function in glycolysis and its link to hemolytic anemia, ACO1's dual role in the TCA cycle and iron regulation, and RPS13's importance in protein synthesis and erythropoiesis. Each protein was identified as a significant node within the network, indicating its potential as a biomarker and therapeutic target. The integration of genomic, proteomic, and clinical data revealed that these proteins play pivotal roles in the molecular mechanisms underlying anemia. GAPDH interacts with iron-regulatory proteins, EEF2 modulates protein synthesis, TPI1 mutations lead to hemolytic anemia, ACO1 regulates iron homeostasis and is linked to sideroblastic anemia, and RPS13 contributes to erythropoiesis. This study explores how specific proteins may contribute to the development and progression of anemia. Rather than reinforcing existing models, it introduces fresh biological clues that could reshape how clinicians interpret and treat this condition. These findings point toward personalized treatment options and offer a more refined lens for evaluating patient needs.
1. Patil SV, Kshirsagar N, Mohite RV, editors. Nutritional anemia: prevalence, causes, and interventions in the pediatric population. Obstetrics and Gynaecology Forum; 2024
2. Kassebaum NJ, Jasrasaria R, Naghavi M, Wulf SK, Johns N, Lozano R, et al. A systematic analysis of global anemia burden from 1990 to 2010. Blood 2014;123:615-24.
3. Abbineni PS, Baid S, Weiss MJ. A moonlighting job for α-globin in blood vessels. Blood 2024;144:834-44.
4. Jeffery CJ. Protein moonlighting: what is it, and why is it important? Philos Trans R Soc B Biol Sci 2018;373:20160523.
5. Gupta MN, Uversky VN. Moonlighting enzymes: when cellular context defines specificity. J Cell Sci 2023;80:130.
6. Conway ME. Emerging moonlighting functions of the branched-chain aminotransferase proteins. J Amino Acids Signal 2021;34:1048-67.
7. Bomblies K, Peichel CL. Genetics of adaptation. Proc Natl Acad Sci USA 2022;119:e2122152119.
8. Liu H, Jeffery CJ. Moonlighting proteins in the fuzzy logic of cellular metabolism. Molecules 2020;25:3440.
9. Zanzoni A, Chapple CE, Brun C. Relationships between predicted moonlighting proteins, human diseases, and comorbidities from a network perspective. Front Physiol 2015;6:171.
10. Eguchi T, Taha EA, Calderwood SK, Ono K. A novel model of cancer drug resistance: oncosomal release of cytotoxic and antibody-based drugs. Biology 2020;9:47.
11. Zhang N, Yu X, Xie J, Xu H. New insights into the role of ferritin in iron homeostasis and neurodegenerative diseases. Mol Neurobiol 2021;58:2812-23.
12. Milenkovic J, Djordjevic B, Stojanovic D, Dunjic O, Petrovski V. Blue moonlighting in the immune response: roles of copper and ceruloplasmin in the pathogenesis of inflammation and immune-mediated diseases. Acta Med Medianae 2022;61.
13. Malhotra H, Kumar M, Chauhan AS, Dhiman A, Chaudhary S, Patidar A, et al. Moonlighting protein glyceraldehyde-3-phosphate dehydrogenase: a cellular rapid-response molecule for maintenance of iron homeostasis in hypoxia. Cell Physiol Biochem 2019;52:517-31.
14. Lyu J, Ni M, Weiss MJ, Xu J. Metabolic regulation of erythrocyte development and disorders. EBioMedicine 2024;131:104153.
15. Haage A, Dhasarathy A. Working a second job: cell adhesion proteins that moonlight in the nucleus. Front Cell Dev Biol 2023;11:1163553.
16. Sriram G, Martinez JA, McCabe ER, Liao JC, Dipple KM. Single-gene disorders: what role could moonlighting enzymes play? Am J Hum Genet 2005;76:911-24.
17. Werelusz P, Galiniak S, Mołoń M. Molecular functions of moonlighting proteins in cell metabolic processes. Biochim Biophys Acta Mol Cell Res 2024;1871:119598.
18. Wang P, Lü J, Yu X. Identification of important nodes in directed biological networks: a network motif approach. PLoS One 2014;9:e106132.
19. Nunes S, Sousa RT, Pesquita C. Multi-domain knowledge graph embeddings for gene-disease association prediction. J Biomed Semantics 2023;14:11.
20. Meng Z, Liu S, Liang S, Jani B, Meng Z. Heterogeneous biomedical entity representation learning for gene–disease association prediction. Brief Bioinform 2024;25:bbae380.
21. Iacobucci I, Monaco V, Cozzolino F, Monti M. From classical to new generation approaches: an excursus of -omics methods for investigation of protein-protein interaction networks. J Proteomics 2021;230:103990
22. Wang M, Wang H, Zheng H. A mini review of node centrality metrics in biological networks. Int J Netw Data Intell 2022;1:99-110.
23. Li Y, Tabatabai ZL, Lee TL, Hatakeyama S, Ohyama C, Chan WY, et al. The Y-encoded TSPY protein: a significant marker potentially plays a role in the pathogenesis of testicular germ cell tumors. Hum Pathol 2007;38:1470-81.
24. Lim JK, Samiei A, Delaidelli A, de Santis JO, Brinkmann V, Carnie CJ, et al. The eEF2 kinase coordinates the DNA damage response to cisplatin by supporting p53 activation. Nat Commun 2024;15:501.
25. Ma Y, Song H, Liu S, Yu W, Feng G, Yang C, et al. A coordinated translational control mediated by eEF2 phosphorylation safeguards erythroid differentiation. Mol Cell Biol 2025;26:4801.
26. Liu Y, Cao Y, Zhang Q, Li X, Wang S. A cytosolic triosephosphate isomerase is a key component in XA3/XA26-mediated resistance. Plant Physiol 2018;178:923-35.
27. Roland BP, Richards KR, Hrizo SL, Eicher S, Barile ZJ, Chang TC, et al. Missense variant in TPI1 causes neurologic deficits through structural changes in the catalytic site and reduced enzyme levels in vivo. Biochim Biophys Acta 2019;1865:2257-66.
28. Fischer C, Volani C, Komlódi T, Seifert M, Demetz E, Valente de Souza L, et al. Dietary iron overload and Hfe−/− related hemochromatosis alter hepatic mitochondrial function. Antioxidants 2021;10:1818.
29. Regev-Rudzki N, Karniely S, Ben-Haim NN, Pines O. Yeast aconitase in two locations and two metabolic pathways. Mol Biol Cell 2005;16:4163-71.
30. Malygin AA, Parakhnevitch NM, Ivanov AV, Eperon IC, Karpova GG. Human ribosomal protein S13 regulates expression of its own gene at the splicing step. Nucleic Acids Res 2007;35:6414-23.
31. Wang J, Yan F. Roles of ribosomal proteins in hematologic disorders and cancers: a review. Exp Hematol Med 2023;3:23-31.
32. KT N, Prasad K, Singh BMK. Analysis of red blood cells from peripheral blood smear images for anemia detection. Med Biol Eng Comput 2022;60:2445-62.
33. Bonilla DA, Moreno Y, Petro JL, Forero DA, Vargas-Molina S, Odriozola-Martínez A, et al. Iron metabolism and immune system biomarkers in exercise stress-induced immunosuppression. Biomedicines 2022;10:724.
34. Garcia NP, Júnior ALS, Soares GAS, Costa TCC, Dos Santos APC, Costa AG, et al. Sickle cell anemia patients display an intricate biomarker network. J Immunol Res 2020;2020:4585704.
35. Chen C, Hou J, Tanner JJ, Cheng J. Bioinformatics methods for mass spectrometry-based proteomics data analysis. Int J Mol Sci 2020;21:2873.
36. Russell G, Veal D, Hancock JT. Is glyceraldehyde-3-phosphate dehydrogenase a central redox mediator? React Oxyg Species 2020;9:48-69.
37. Zhu J, Wang Y, Rivett A, Yang G. H2S regulation of iron homeostasis by IRP1 improves vascular smooth muscle cell functions. Cell Signal 2023;110:110826.
38. INVALID CITATION
39. Reisz JA, Wither MJ, Dzieciatkowska M, Nemkov T, Issaian A, Yoshida T, et al. Oxidative modifications of GAPDH regulate metabolic reprogramming of stored red blood cells. Blood 2016;128:e32-e42.
40. Myers TD, Ferguson C, Gliniak E, Homanics GE, Palladino MJ. Murine model of triosephosphate isomerase deficiency with anemia. Curr Res Neurobiol 2022;3:100062.
41. McCarty K. A novel approach to triosephosphate isomerase deficiency, 2022
42. Selamioğlu A, Karaca M, Balcı MC, Körbeyli HK, Durmuş A, Yıldız EP, et al. Triosephosphate isomerase deficiency: E105D mutation and review. Mol Syndromol 2023;14:231-8.
43. INVALID CITATION
44. Driessen J, Kersten MJ, Visser L, van den Berg A, Tonino SH, Zijlstra JM, et al. Prognostic value of TARC and PET parameters in Hodgkin lymphoma. Leukemia 2022;36:2853-62.
45. Jung SJ, Seo Y, Lee KC, Lee D, Roe JH. Essential function of Aco2 in mitochondrial translation. FEBS Lett 2015;589:822-8.
46. Oskarsson GR, Oddsson A, Magnusson MK, Kristjansson RP, Halldorsson GH, Ferkingstad E, et al. Mutations in ACO1 and erythropoiesis. Commun Biol 2020;3:189.
47. Yamamoto M, Tanaka H, Toki Y, Hatayama M, Ito S, Addo L, et al. Iron-induced epigenetic abnormalities in mouse bone marrow. Int J Hematol 2016;104:491-501.
48. Richardson CL. Mechanistic and therapeutic studies related to anemia of chronic disease and inflammation. Charlottesville: University of Virginia; 2013.
49. Wang M, Chen X, Wu Y, Zheng Q, Chen W, Yan Y, et al. RpS13 controls germline stem cell niche homeostasis. Cell Prolif 2020;53:e12899.
50. Liu Y, Karlsson S. Perspectives of current understanding and therapeutics of Diamond-Blackfan anemia. J Leukoc Biol 2024;38:1-9.
51. Horos R, von Lindern M. Molecular mechanisms of pathology and treatment in Diamond-Blackfan anemia. Br J Haematol 2012;159:514-27.
52. Hong Y, Lin Q, Zhang Y, Liu J, Zheng Z. Research progress of ribosomal proteins in reproductive development. Int J Mol Sci 2024;25:13151.
53. Xharra S, Behluli E, Nefic H, Hadziselimovic R, Sopi-Xharra K, Temaj G. When ribosomal proteins go bad: mutation of RPS23 in different diseases, 2020.
2. Kassebaum NJ, Jasrasaria R, Naghavi M, Wulf SK, Johns N, Lozano R, et al. A systematic analysis of global anemia burden from 1990 to 2010. Blood 2014;123:615-24.
3. Abbineni PS, Baid S, Weiss MJ. A moonlighting job for α-globin in blood vessels. Blood 2024;144:834-44.
4. Jeffery CJ. Protein moonlighting: what is it, and why is it important? Philos Trans R Soc B Biol Sci 2018;373:20160523.
5. Gupta MN, Uversky VN. Moonlighting enzymes: when cellular context defines specificity. J Cell Sci 2023;80:130.
6. Conway ME. Emerging moonlighting functions of the branched-chain aminotransferase proteins. J Amino Acids Signal 2021;34:1048-67.
7. Bomblies K, Peichel CL. Genetics of adaptation. Proc Natl Acad Sci USA 2022;119:e2122152119.
8. Liu H, Jeffery CJ. Moonlighting proteins in the fuzzy logic of cellular metabolism. Molecules 2020;25:3440.
9. Zanzoni A, Chapple CE, Brun C. Relationships between predicted moonlighting proteins, human diseases, and comorbidities from a network perspective. Front Physiol 2015;6:171.
10. Eguchi T, Taha EA, Calderwood SK, Ono K. A novel model of cancer drug resistance: oncosomal release of cytotoxic and antibody-based drugs. Biology 2020;9:47.
11. Zhang N, Yu X, Xie J, Xu H. New insights into the role of ferritin in iron homeostasis and neurodegenerative diseases. Mol Neurobiol 2021;58:2812-23.
12. Milenkovic J, Djordjevic B, Stojanovic D, Dunjic O, Petrovski V. Blue moonlighting in the immune response: roles of copper and ceruloplasmin in the pathogenesis of inflammation and immune-mediated diseases. Acta Med Medianae 2022;61.
13. Malhotra H, Kumar M, Chauhan AS, Dhiman A, Chaudhary S, Patidar A, et al. Moonlighting protein glyceraldehyde-3-phosphate dehydrogenase: a cellular rapid-response molecule for maintenance of iron homeostasis in hypoxia. Cell Physiol Biochem 2019;52:517-31.
14. Lyu J, Ni M, Weiss MJ, Xu J. Metabolic regulation of erythrocyte development and disorders. EBioMedicine 2024;131:104153.
15. Haage A, Dhasarathy A. Working a second job: cell adhesion proteins that moonlight in the nucleus. Front Cell Dev Biol 2023;11:1163553.
16. Sriram G, Martinez JA, McCabe ER, Liao JC, Dipple KM. Single-gene disorders: what role could moonlighting enzymes play? Am J Hum Genet 2005;76:911-24.
17. Werelusz P, Galiniak S, Mołoń M. Molecular functions of moonlighting proteins in cell metabolic processes. Biochim Biophys Acta Mol Cell Res 2024;1871:119598.
18. Wang P, Lü J, Yu X. Identification of important nodes in directed biological networks: a network motif approach. PLoS One 2014;9:e106132.
19. Nunes S, Sousa RT, Pesquita C. Multi-domain knowledge graph embeddings for gene-disease association prediction. J Biomed Semantics 2023;14:11.
20. Meng Z, Liu S, Liang S, Jani B, Meng Z. Heterogeneous biomedical entity representation learning for gene–disease association prediction. Brief Bioinform 2024;25:bbae380.
21. Iacobucci I, Monaco V, Cozzolino F, Monti M. From classical to new generation approaches: an excursus of -omics methods for investigation of protein-protein interaction networks. J Proteomics 2021;230:103990
22. Wang M, Wang H, Zheng H. A mini review of node centrality metrics in biological networks. Int J Netw Data Intell 2022;1:99-110.
23. Li Y, Tabatabai ZL, Lee TL, Hatakeyama S, Ohyama C, Chan WY, et al. The Y-encoded TSPY protein: a significant marker potentially plays a role in the pathogenesis of testicular germ cell tumors. Hum Pathol 2007;38:1470-81.
24. Lim JK, Samiei A, Delaidelli A, de Santis JO, Brinkmann V, Carnie CJ, et al. The eEF2 kinase coordinates the DNA damage response to cisplatin by supporting p53 activation. Nat Commun 2024;15:501.
25. Ma Y, Song H, Liu S, Yu W, Feng G, Yang C, et al. A coordinated translational control mediated by eEF2 phosphorylation safeguards erythroid differentiation. Mol Cell Biol 2025;26:4801.
26. Liu Y, Cao Y, Zhang Q, Li X, Wang S. A cytosolic triosephosphate isomerase is a key component in XA3/XA26-mediated resistance. Plant Physiol 2018;178:923-35.
27. Roland BP, Richards KR, Hrizo SL, Eicher S, Barile ZJ, Chang TC, et al. Missense variant in TPI1 causes neurologic deficits through structural changes in the catalytic site and reduced enzyme levels in vivo. Biochim Biophys Acta 2019;1865:2257-66.
28. Fischer C, Volani C, Komlódi T, Seifert M, Demetz E, Valente de Souza L, et al. Dietary iron overload and Hfe−/− related hemochromatosis alter hepatic mitochondrial function. Antioxidants 2021;10:1818.
29. Regev-Rudzki N, Karniely S, Ben-Haim NN, Pines O. Yeast aconitase in two locations and two metabolic pathways. Mol Biol Cell 2005;16:4163-71.
30. Malygin AA, Parakhnevitch NM, Ivanov AV, Eperon IC, Karpova GG. Human ribosomal protein S13 regulates expression of its own gene at the splicing step. Nucleic Acids Res 2007;35:6414-23.
31. Wang J, Yan F. Roles of ribosomal proteins in hematologic disorders and cancers: a review. Exp Hematol Med 2023;3:23-31.
32. KT N, Prasad K, Singh BMK. Analysis of red blood cells from peripheral blood smear images for anemia detection. Med Biol Eng Comput 2022;60:2445-62.
33. Bonilla DA, Moreno Y, Petro JL, Forero DA, Vargas-Molina S, Odriozola-Martínez A, et al. Iron metabolism and immune system biomarkers in exercise stress-induced immunosuppression. Biomedicines 2022;10:724.
34. Garcia NP, Júnior ALS, Soares GAS, Costa TCC, Dos Santos APC, Costa AG, et al. Sickle cell anemia patients display an intricate biomarker network. J Immunol Res 2020;2020:4585704.
35. Chen C, Hou J, Tanner JJ, Cheng J. Bioinformatics methods for mass spectrometry-based proteomics data analysis. Int J Mol Sci 2020;21:2873.
36. Russell G, Veal D, Hancock JT. Is glyceraldehyde-3-phosphate dehydrogenase a central redox mediator? React Oxyg Species 2020;9:48-69.
37. Zhu J, Wang Y, Rivett A, Yang G. H2S regulation of iron homeostasis by IRP1 improves vascular smooth muscle cell functions. Cell Signal 2023;110:110826.
38. INVALID CITATION
39. Reisz JA, Wither MJ, Dzieciatkowska M, Nemkov T, Issaian A, Yoshida T, et al. Oxidative modifications of GAPDH regulate metabolic reprogramming of stored red blood cells. Blood 2016;128:e32-e42.
40. Myers TD, Ferguson C, Gliniak E, Homanics GE, Palladino MJ. Murine model of triosephosphate isomerase deficiency with anemia. Curr Res Neurobiol 2022;3:100062.
41. McCarty K. A novel approach to triosephosphate isomerase deficiency, 2022
42. Selamioğlu A, Karaca M, Balcı MC, Körbeyli HK, Durmuş A, Yıldız EP, et al. Triosephosphate isomerase deficiency: E105D mutation and review. Mol Syndromol 2023;14:231-8.
43. INVALID CITATION
44. Driessen J, Kersten MJ, Visser L, van den Berg A, Tonino SH, Zijlstra JM, et al. Prognostic value of TARC and PET parameters in Hodgkin lymphoma. Leukemia 2022;36:2853-62.
45. Jung SJ, Seo Y, Lee KC, Lee D, Roe JH. Essential function of Aco2 in mitochondrial translation. FEBS Lett 2015;589:822-8.
46. Oskarsson GR, Oddsson A, Magnusson MK, Kristjansson RP, Halldorsson GH, Ferkingstad E, et al. Mutations in ACO1 and erythropoiesis. Commun Biol 2020;3:189.
47. Yamamoto M, Tanaka H, Toki Y, Hatayama M, Ito S, Addo L, et al. Iron-induced epigenetic abnormalities in mouse bone marrow. Int J Hematol 2016;104:491-501.
48. Richardson CL. Mechanistic and therapeutic studies related to anemia of chronic disease and inflammation. Charlottesville: University of Virginia; 2013.
49. Wang M, Chen X, Wu Y, Zheng Q, Chen W, Yan Y, et al. RpS13 controls germline stem cell niche homeostasis. Cell Prolif 2020;53:e12899.
50. Liu Y, Karlsson S. Perspectives of current understanding and therapeutics of Diamond-Blackfan anemia. J Leukoc Biol 2024;38:1-9.
51. Horos R, von Lindern M. Molecular mechanisms of pathology and treatment in Diamond-Blackfan anemia. Br J Haematol 2012;159:514-27.
52. Hong Y, Lin Q, Zhang Y, Liu J, Zheng Z. Research progress of ribosomal proteins in reproductive development. Int J Mol Sci 2024;25:13151.
53. Xharra S, Behluli E, Nefic H, Hadziselimovic R, Sopi-Xharra K, Temaj G. When ribosomal proteins go bad: mutation of RPS23 in different diseases, 2020.
| Files | ||
| Issue | Vol 63 No 6 (2025) | |
| Section | Original Articles | |
| DOI | https://doi.org/10.18502/acta.v63i6.20675 | |
| Keywords | ||
| Anemia Bioinformatics Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) Eukaryotic elongation factor 2 (EEF2) Inflammation Hemolytic anemia | ||
| Rights and permissions | |
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Bahrami A, Bossaghzadeh F, Golbashirzadeh M. Unraveling the Anemia Nexus: Bioinformatics-Driven Discovery of Key Protein Interactions and Therapeutic Targets. Acta Med Iran. 2025;63(6):330-344.
