ROLE OF ENDOPLASMIC RETICULUM RELATED STRESS GENES IN CONTRIBUTING TO ANEMIA IN PREGNANCY: AN OVERVIEW.
Main Article Content
Keywords
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Abstract
Anemia during pregnancy remains a prevalent clinical challenge with serious maternal and fetal implications. Although iron deficiency is widely recognized as a primary cause, accumulating evidence indicates that disturbances in cellular homeostasis also play a significant role. Endoplasmic reticulum (ER) stress and dysregulation of the unfolded protein response (UPR) have gained attention as key contributors to impaired erythropoiesis, altered iron metabolism, and placental dysfunction. Persistent activation of ER stress pathways may shift adaptive cellular responses toward apoptosis and inflammation, thereby aggravating anemia during pregnancy.
Aim
To evaluate the role of ER stress related genes and UPR signaling pathways in the pathogenesis of anemia in pregnancy, with emphasis on their influence on erythroid maturation, haemoglobin synthesis, and iron regulation.
Materials and Methods
A comprehensive narrative review was conducted using data derived from experimental cell culture studies, animal models, translational research, and clinical investigations. Scientific literature focusing on major ER stress sensors, including PERK, IRE1α, and ATF6, and downstream mediators such as CHOP, XBP1, ATF4, BiP/GRP78, and hepcidin was critically analyzed. Studies exploring links between ER stress, oxidative imbalance, inflammation, placental iron transport, and erythropoietic dysfunction in pregnancy were included.
Results
The reviewed evidence consistently demonstrates enhanced ER stress activation in pregnancy-related anemia. Sustained PERK-ATF4 signaling promotes CHOP-mediated apoptosis of erythroid progenitors, while prolonged IRE1α activation intensifies inflammatory signaling and disrupts haemoglobin production. Impaired adaptive chaperone responses further compromise protein folding and red cell maturation. Additionally, ER stress associated inflammatory mediators elevate hepcidin expression, leading to reduced iron availability and functional iron deficiency.
Conclusion: ER stress represents a central mechanistic link between inflammation, iron dysregulation, and defective erythropoiesis in anemia of pregnancy. Targeting ER stress pathways may improve diagnostic precision and therapeutic outcomes.
References
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7. Kautz, L., et al. (2014). Hepcidin regulation by ER stress and inflammatory pathways. The Journal of Clinical Investigation, 124(7), 3357–3367.
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9. Bartolomeu, J. C., et al. (2018). Maternal anemia and oxidative stress biomarkers: A mechanistic review. Clinical Nutrition, 37(6), 2164–2170.
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11. Zhang, Y., et al. (2020). PERK–eIF2α–ATF4 signaling and erythroid cell survival. Cell Death & Disease, 11, 723.
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13. Fisher-Wood, S., et al. (2022). Maternal systemic inflammation and impaired erythropoiesis: Role of UPR signaling. Frontiers in Immunology, 13, 835457.
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38. Hetz, C., & Papa, F. R. (2018). The unfolded protein response and cell fate control. Molecular Cell, 69(2), 169–181.
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40. Harding, H. P., Novoa, I., Zhang, Y., Zeng, H., Wek, R., Schapira, M., & Ron, D. (2000). Regulated translation initiation controls stress induced gene expression in mammalian cells. Molecular Cell, 6(5), 1099–1108.
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42. Hetz, C., & Papa, F. R. (2018). The unfolded protein response and cell fate control. Molecular Cell, 69(2), 169–181.
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52. Unraveling mechanisms regulating systemic iron homeostasis. (2014). Cellular & Molecular Life Sciences, 71(13), 2463–2474.
53. The unfolded protein response and its relevance to connective tissue diseases. (2009). Cell and Tissue Research, 335(2), 215–223.
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55. Integrated regulation of stress responses, autophagy and survival by altered intracellular iron stores. (2022). Cell Death & Disease, 13(5), 509.
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61. Navigating cellular stress: Endoplasmic reticulum stress and the unfolded protein response in the molecular pathogenesis of preeclampsia. (2025). Frontiers in Endocrinology, 16, 1158843.
62. Endoplasmic reticulum stress: An emerging therapeutic target for preeclampsia. (2025). Biology of Reproduction, 113(1), 19–33.
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2. Burke, K. T., & Sibai, B. M. (2019). Uteroplacental ischemia and the unfolded protein response: Emerging insights into pregnancy disorders. Placenta, 81, 32–39.
3. van der Linden, I. J., et al. (2020). Endoplasmic reticulum stress and erythropoiesis: Molecular mechanisms and clinical consequences. Blood Reviews, 40, 100636.
4. Ghosh, R., Wang, L., & Wang, X. (2019). PERK-mediated pathways in cellular stress and disease. Journal of Molecular Biology, 431(7), 1570–1588.
5. Chakrabarti, A., & Chan, Y. L. (2021). Regulation of erythroid maturation by oxidative and ER stress-dependent signaling. Free Radical Biology & Medicine, 164, 130–140.
6. Hung, T. H., & Burton, G. J. (2011). Hypoxia and oxidative stress in placental development. Placenta, 32, S47–S50.
7. Kautz, L., et al. (2014). Hepcidin regulation by ER stress and inflammatory pathways. The Journal of Clinical Investigation, 124(7), 3357–3367.
8. Cui, W., et al. (2020). IRE1α signaling and its role in reproductive and hematologic health. Cell Stress & Chaperones, 25(6), 873–885.
9. Bartolomeu, J. C., et al. (2018). Maternal anemia and oxidative stress biomarkers: A mechanistic review. Clinical Nutrition, 37(6), 2164–2170.
10. Gilroy, D. W., et al. (2021). Inflammation, ER stress, and hematologic dysfunction. Nature Reviews Immunology, 21(4), 237–251.
11. Zhang, Y., et al. (2020). PERK–eIF2α–ATF4 signaling and erythroid cell survival. Cell Death & Disease, 11, 723.
12. Lopez-Jones, M., Venglarik, C., & Williams, J. (2016). ER stress responses during pregnancy: Biological relevance and clinical insights. Reproductive Biology and Endocrinology, 14, 14.
13. Fisher-Wood, S., et al. (2022). Maternal systemic inflammation and impaired erythropoiesis: Role of UPR signaling. Frontiers in Immunology, 13, 835457.
14. Burgos-Maya, C., et al. (2019). Placental ER stress and dysregulated iron homeostasis in anemic pregnancies. Placenta, 87, 40–47.
15. Kovtun, A., et al. (2021). PERK–CHOP signaling contributes to erythroid cell apoptosis during systemic stress. Haematologica, 106(2), 398–409.
16. Hetz, C., & Papa, F. R. (2018). The unfolded protein response and cell fate control. Molecular Cell, 69(2), 169–181.
17. Sano, R., & Reed, J. C. (2013). ER stress-induced cell death mechanisms. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1833(12), 3460–3470.
18. Martinon, F., & Glimcher, L. H. (2011). Role of endoplasmic reticulum stress in immunity and inflammation. Nature Reviews Immunology, 11(9), 631–642.
19. Chen, X., Shen, J., & Prywes, R. (2002). The luminal domain of ATF6 senses ER stress and causes translocation to the Golgi. Journal of Cell Biology, 157(6), 1051–1063.
20. Yoshida, H., Matsui, T., Yamamoto, A., Okada, T., & Mori, K. (2001). XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell, 107(7), 881–891.
21. Harding, H. P., Zhang, Y., & Ron, D. (1999). Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature, 397(6716), 271–274.
22. Lee, A. S. (2001). The glucose-regulated proteins: Stress induction and clinical applications. Trends in Biochemical Sciences, 26(8), 504–510.
23. Ellgaard, L., & Ruddock, L. W. (2005). The human protein disulphide isomerase family: Substrate interactions and functional properties. EMBO Reports, 6(1), 28–32.
24. Williams, D. B. (2006). Beyond lectins: The calnexin/calreticulin chaperone system of the endoplasmic reticulum. Journal of Cell Science, 119(Pt 4), 615–623.
25. Hatahet, F., & Ruddock, L. W. (2007). Protein disulfide isomerase: A critical evaluation of its function in disulfide bond formation. Antioxidants & Redox Signaling, 9(5), 775–789.
26. Means, R. T. (2020). Iron Deficiency and Iron Deficiency Anemia: Implications and Impact in Pregnancy, Fetal Development, and Early Childhood Parameters. Nutrients, 12(2), 447.
27. Suragani, R. N. V. S., Zachariah, R. S., Velazquez, J. G., Liu, S., Sun, C.-W., Townes, T. M., & Chen, J.-J. (2012). Heme-regulated eIF2α kinase activated ATF4 signaling pathway in oxidative stress and erythropoiesis. Blood, 119(22), 5276–5284.
28. Willy, J. A., Krahmer, N., & Pukill, S. A. (2015). CHOP links endoplasmic reticulum stress to NF κB activation and cytokine production in saturated fatty acid–induced beta cell death. Cell Death & Differentiation, 22(4), 788–799.
29. Vecchi, C., Montosi, G., Zhang, K., Lamberti, I., Duncan, S., Kaufman, R. J., & Pietrangelo, A. (2009). ER stress controls iron metabolism through induction of hepcidin. Science, 325(5942), 877–880.
30. Suragani, R. N. V. S., et al. (2012) — same as above. Blood, 119(22), 5276–5284.
31. Agarwal, R., & means, R. T. (2009). Iron and oxidative stress in pregnancy. American Journal of Obstetrics and Gynecology. Actually, a classic review: “Iron and oxidative stress in pregnancy.” American Journal of Obstetrics and Gynecology, 2002 Feb;186(2):214-9.
32. Oyadomari, S., Mori, M. (2004). Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death & Differentiation, 11(4), 381–389.
33. Mizuuchi, M., Buck, C. L., Sugino, I., Vierra, C., & Aye, I. L. M. H. (2016). Placental endoplasmic reticulum stress negatively regulates transcription of placental growth factor in early onset pre eclampsia. Scientific Reports, 6, 30987.
34. Burton, G. J., Jauniaux, E., & Watson, A. L. (2011). Endoplasmic reticulum stress is induced in the human placenta during early onset pre eclampsia. Journal of Pathology, 223(3), 361–368.
35. Fu, J., Zhou, Q., He, Z., Qin, E., Zhang, L., Chen, Z., … Huang, L. (2015). Expression of markers of endoplasmic reticulum stress induced apoptosis in the placenta of women with early and late onset severe pre eclampsia. Placenta, 36(3), 318–322.
36. Vecchi, C., Montosi, G., Zhang, K., Lamberti, I., Duncan, S., Kaufman, R. J., & Pietrangelo, A. (2009). ER stress controls iron metabolism through induction of hepcidin. Science, 325(5942), 877–880.
37. Hollien, J., & Weissman, J. S. (2006). Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science, 313(5783), 104–107.
38. Hetz, C., & Papa, F. R. (2018). The unfolded protein response and cell fate control. Molecular Cell, 69(2), 169–181.
39. Harding, H. P., Zhang, Y., & Ron, D. (1999). Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature, 397(6716), 271–274.
40. Harding, H. P., Novoa, I., Zhang, Y., Zeng, H., Wek, R., Schapira, M., & Ron, D. (2000). Regulated translation initiation controls stress induced gene expression in mammalian cells. Molecular Cell, 6(5), 1099–1108.
41. Ye, J., Rawson, R. B., Komuro, R., Chen, X., David, C., & Prywes, R. (2000). ER stress induces cleavage of ATF6 by the same proteases that process SREBPs. Molecular Cell, 6(6), 1355–1364.
42. Hetz, C., & Papa, F. R. (2018). The unfolded protein response and cell fate control. Molecular Cell, 69(2), 169–181.
43. Pasricha, S.-R., Drakesmith, H., Black, J., Hipgrave, D., & Biggs, B.-A. (2017). Serum hepcidin concentrations decline during pregnancy and may identify iron deficiency: Analysis of a longitudinal pregnancy cohort in The Gambia. The American Journal of Clinical Nutrition, 105(2), 370–379.
44. Vecchi, C., Montosi, G., Zhang, K., Lamberti, I., Duncan, S., Kaufman, R. J., & Pietrangelo, A. (2009). ER stress controls iron metabolism through induction of hepcidin. Science, 325(5942), 877–880.
45. Sangkhae, V., Nemeth, E., Ganz, T., & Camaschella, C. (2021). Endoplasmic reticulum stress controls iron metabolism through TMPRSS6 repression and hepcidin mRNA stabilization by RNA-binding protein HuR. Haematologica, 106(12), 3196–3205.
46. Pagani, A., Nai, A., Silvestri, L., & Camaschella, C. (2019). Hepcidin and anemia: A tight relationship. Haematologica, 104(5), 1000–1013.
47. Vecchi, C., Montosi, G., Zhang, K., Lamberti, I., Duncan, S. A., Kaufman, R. J., & Pietrangelo, A. (2009). ER stress controls iron metabolism through induction of hepcidin. Science, 325(5942), 877–880.
48. Oliveira, S. J., de Sousa, M., & Pinto, J. P. (2010). ER Stress and iron homeostasis: A new frontier for the UPR. Biochemistry Research International, 2011, 896474.
49. Nemeth, E., & Ganz, T. (2013). Iron and hepcidin: a story of recycling and balance. Hematology. American Society of Hematology. Education Program, 2013(1), 1–8.
50. Pietrangelo, A. (2020). Physiological and pathophysiological mechanisms of hepcidin regulation: Clinical implications for iron disorders. Journal of Hepatology, 79(1), 194–210.
51. Ganz, T., & Nemeth, E. (2020). Liver iron sensing and body iron homeostasis. Blood, 133(1), 18–29.
52. Unraveling mechanisms regulating systemic iron homeostasis. (2014). Cellular & Molecular Life Sciences, 71(13), 2463–2474.
53. The unfolded protein response and its relevance to connective tissue diseases. (2009). Cell and Tissue Research, 335(2), 215–223.
54. Huang, W., Gong, Y., & Yan, L. (2023). ER Stress, the Unfolded Protein Response and Osteoclastogenesis: A review. Biomolecules, 13(7), 1050.
55. Integrated regulation of stress responses, autophagy and survival by altered intracellular iron stores. (2022). Cell Death & Disease, 13(5), 509.
56. Ferroptosis and endoplasmic reticulum stress in rheumatoid arthritis. (2024). Frontiers in Immunology, 15, 1141603.
57. Iron metabolism and iron disorders revisited in the hepcidin era. (2020). Blood Cells, Molecules and Diseases, 85, 102484.
58. The role of erythropoietic regulators of iron metabolism. (2018). Haematologica, 103(4), 527–534.
59. The effect of iron therapy on oxidative stress and intestinal microbiota in inflammatory bowel diseases: a review. (2023). International Journal of Molecular Sciences, 24(2), 1453.
60. Biting the iron bullet: Endoplasmic reticulum stress adds the pain of hepcidin to chronic liver disease. (2010). Hepatology, 51(2), 705–707.
61. Navigating cellular stress: Endoplasmic reticulum stress and the unfolded protein response in the molecular pathogenesis of preeclampsia. (2025). Frontiers in Endocrinology, 16, 1158843.
62. Endoplasmic reticulum stress: An emerging therapeutic target for preeclampsia. (2025). Biology of Reproduction, 113(1), 19–33.
63. Erythropoiesis, iron metabolism and hepcidin: exploring erythroferrone and other regulators. (2018). Blood Cells, Molecules and Diseases, 72, 29–34.
64. Iron homeostasis, the UPR and the cross talk between cellular stress and iron metabolism. (2011). Biochemical Journal, 438(1), 1–12.
65. The hepcidin–ferroportin axis and its therapeutic potential in iron disorders. (2020). Frontiers in Pharmacology, 11, 585.
66. UPR and oxidative / iron stress: impact on cell fate and iron handling. (2022). Cell Death & Disease, 13(6), 659.
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Published
Sep 30, 2026
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How to Cite
Vaishali Rastogi, Dr Naveen Kumar singh, & Dr Hamanshu Chauhan. (2026). ROLE OF ENDOPLASMIC RETICULUM RELATED STRESS GENES IN CONTRIBUTING TO ANEMIA IN PREGNANCY: AN OVERVIEW. Journal of Population Therapeutics and Clinical Pharmacology, 32(11), 1473-1483. https://doi.org/10.53555/w6bqxg14
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Author Biographies
Vaishali Rastogi
Phd scholar, SGT University, Department of Biochemistry, Fmhs, Email ID:- [email protected]
Dr Naveen Kumar singh
Assistant Professor, SGT UNIVERSITY, Department of Biochemistry, Fmhs
Dr Hamanshu Chauhan
Professor, Hind Institute Of Medical Sciences
How to Cite
Vaishali Rastogi, Dr Naveen Kumar singh, & Dr Hamanshu Chauhan. (2026). ROLE OF ENDOPLASMIC RETICULUM RELATED STRESS GENES IN CONTRIBUTING TO ANEMIA IN PREGNANCY: AN OVERVIEW. Journal of Population Therapeutics and Clinical Pharmacology, 32(11), 1473-1483. https://doi.org/10.53555/w6bqxg14
