Research Progress on Nrf2 and Oxidative Stress in Preeclampsia

doi:10.12280/gjfckx.20251151

Abstract

Abstract:

Oxidative stress is a key pathophysiological mechanism in preeclampsia. Therefore, antioxidant stress holds significant importance for the prevention and treatment of preeclampsia and its related complications. This paper systematically reviews the molecular mechanisms and pathophysiological significance of nuclear factor-erythroid 2-related factor 2 (Nrf2) in regulating oxidative stress in preeclampsia. Recent studies have found that the signaling pathway constituted by Nrf2 and its negative regulatory protein, Kelch-like ECH-associated protein 1 (KEAP1), is frequently dysregulated or functionally impaired in placental tissues of preeclampsia patients and in animal models. This impairment leads to the inhibited transcriptional activation of downstream antioxidant genes, such as heme oxygenase-1 and NAD(P)H:quinone oxidoreductase 1, thereby exacerbating placental oxidative damage. Further research indicates that Nrf2 not only regulates the gene expression profile driven by the antioxidant response element (ARE) but also participates in placental formation and remodeling by influencing vascular endothelial cell function and trophoblast apoptosis. Nrf2 is a key nodal molecule linking oxidative stress to the pathological progression of preeclampsia, and its activation status is closely associated with disease severity and progression.

Key words: Pre-eclampsia, Oxidative stress, Placenta, Endothelial cells, Nuclear factor-erythroid 2-related factor 2

REN Yu-xi, HU Li-yan, REN Yan-xu. Research Progress on Nrf2 and Oxidative Stress in Preeclampsia[J]. Journal of International Obstetrics and Gynecology, 2026, 53(1): 89-92.

References 25

[1]	Palmiero P, Caretto P, Ciccone MM, et al. Long-Term Cardiovascular Risk and Maternal History of Pre-Eclampsia[J]. J Clin Med, 2025, 14(9):3121. doi: 10.3390/jcm14093121.
[2]	Hoang DM, Pham PT, Bach TQ, et al. Stem cell-based therapy for human diseases[J]. Signal Transduct Target Ther, 2022, 7(1):272. doi: 10.1038/s41392-022-01134-4.
[3]	Sultana Z, Qiao Y, Maiti K, et al. Involvement of oxidative stress in placental dysfunction, the pathophysiology of fetal death and pregnancy disorders[J]. Reproduction, 2023, 166(2):R25-R38. doi: 10.1530/REP-22-0278.
[4]	Morgenstern C, Lastres-Becker I, Demirdöğen BC, et al. Biomarkers of NRF2 signalling: Current status and future challenges[J]. Redox Biol, 2024, 72:103134. doi: 10.1016/j.redox.2024.103134.
[5]	Mundal SB, Rakner JJ, Silva GB, et al. Divergent Regulation of Decidual Oxidative-Stress Response by NRF2 and KEAP1 in Preeclampsia with and without Fetal Growth Restriction[J]. Int J Mol Sci, 2022, 23(4):1966. doi: 10.3390/ijms23041966.
[6]	Xiao JL, Liu HY, Sun CC, et al. Regulation of Keap1-Nrf2 signaling in health and diseases[J]. Mol Biol Rep, 2024, 51(1):809. doi: 10.1007/s11033-024-09771-4.
[7]	Tossetta G, Fantone S, Piani F, et al. Modulation of NRF2/KEAP1 Signaling in Preeclampsia[J]. Cells, 2023, 12(11):1545. doi: 10.3390/cells12111545.
[8]	O'Rourke SA, Shanley LC, Dunne A. The Nrf2-HO-1 system and inflammaging[J]. Front Immunol, 2024, 15:1457010. doi: 10.3389/fimmu.2024.1457010.
[9]	严梅, 伍班名. 二甲双胍通过Nrf2/HO-1/NQO1通路减轻子痫前期大鼠胎盘组织氧化应激损伤[J]. 现代医学, 2022, 50(5):597-603. doi: 10.3969/j.issn.1671-7562.2022.05.012.
[10]	Liu L, Wang R, Xu R, et al. Procyanidin B2 ameliorates endothelial dysfunction and impaired angiogenesis via the Nrf2/PPARγ/sFlt-1 axis in preeclampsia[J]. Pharmacol Res, 2022, 177:106127. doi: 10.1016/j.phrs.2022.106127.
[11]	He L, Wu X, Zhan F, et al. Protective role of metformin in preeclampsia via the regulation of NF-κB/sFlt-1 and Nrf2/HO-1 signaling pathways by activating AMPK[J]. Placenta, 2023, 143:91-99. doi: 10.1016/j.placenta.2023.10.003. pmid: 37866322
[12]	Liu X, Bai Y, Chen H, et al. Identification of potential biomarkers associated with oxidative stress in the pathogenesis of pre-eclampsia[J]. Medicine(Baltimore), 2025, 104(10):e41784. doi: 10.1097/MD.0000000000041784.
[13]	Yang Y, Jin H, Qiu Y, et al. Reactive Oxygen Species are Essential for Placental Angiogenesis During Early Gestation[J]. Oxid Med Cell Longev, 2022, 2022:4290922. doi: 10.1155/2022/4290922.
[14]	Torres-Torres J, Espino-Y-Sosa S, Martinez-Portilla R, et al. A Narrative Review on the Pathophysiology of Preeclampsia[J]. Int J Mol Sci, 2024, 25(14):7569. doi: 10.3390/ijms25147569.
[15]	Xu X, Liu S, Gao Y, et al. Epigallocatechin gallate (EGCG) alleviates inflammation and endothelial dysfunction and improves pregnancy outcomes in preeclampsia (PE)-like rats via eNOS/Nrf2/HO-1 pathway[J]. J Reprod Immunol, 2024, 164:104263. doi: 10.1016/j.jri.2024.104263.
[16]	Fiorelli S, Porro B, Cosentino N, et al. Activation of Nrf2/HO-1 Pathway and Human Atherosclerotic Plaque Vulnerability:an In Vitro and In Vivo Study[J]. Cells, 2019, 8(4):356. doi: 10.3390/cells8040356.
[17]	Kondratenko ND, Zinovkina LA, Zinovkin RA. Transcription Factor NRF2 in Endothelial Functions[J]. Mol Biol(Mosk), 2023, 57(6):1058-1076.
[18]	Zhang Y, Liang B, Meng F, et al. Effects of Nrf-2 expression in trophoblast cells and vascular endothelial cells in preeclampsia[J]. Am J Transl Res, 2021, 13(3):1006-1021. pmid: 33841636
[19]	Martínez-Casales M, Hernanz R, Alonso MJ. Vascular and Macrophage Heme Oxygenase-1 in Hypertension: A Mini-Review[J]. Front Physiol, 2021, 12:643435. doi: 10.3389/fphys.2021.643435.
[20]	Afrose D, Alfonso-Sánchez S, McClements L. Targeting oxidative stress in preeclampsia[J]. Hypertens Pregnancy, 2025, 44(1):2445556. doi: 10.1080/10641955.2024.2445556.
[21]	Kornacki J, Olejniczak O, Sibiak R, et al. Pathophysiology of Pre-Eclampsia-Two Theories of the Development of the Disease[J]. Int J Mol Sci, 2023, 25(1):307. doi: 10.3390/ijms25010307.
[22]	Acar N, Soylu H, Edizer I, et al. Expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and peroxiredoxin 6 (Prdx6) proteins in healthy and pathologic placentas of human and rat[J]. Acta Histochem, 2014, 116(8):1289-1300. doi: 10.1016/j.acthis.2014.07.012. pmid: 25171874
[23]	Qiu D, Wu J, Li M, et al. Impaction of factors associated with oxidative stress on the pathogenesis of gestational hypertension and preeclampsia: A Chinese patients based study[J]. Medicine(Baltimore), 2021, 100(11):e23666. doi: 10.1097/MD.0000000000023666.
[24]	文清, 柒铭铭, 赖慧敏, 等. 白藜芦醇在子痫前期中的作用机制及研究进展[J]. 国际妇产科学杂志, 2021, 48(4):371-375. doi: 10.12280/gjfckx.20201129.
[25]	Wang H, Li M, Chen P, et al. Anti-inflammatory and Antioxidant Effects of Pyrroloquinoline Quinone in L-NAME-Induced Preeclampsia-Like Rat Model[J]. Reprod Sci, 2022, 29(2):578-585. doi: 10.1007/s43032-021-00743-8.