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Review Open Access

Role of ubiquitin‑proteasome system in preeclampsia (Review)

  • Authors:
    • Chang-Zhu Pei
    • Xiao-Xing Song
    • Hao Xu
    • Kwang-Hyun Baek
  • View Affiliations / Copyright

    Affiliations: Department of Gynecology, Lianyungang Maternal and Child Health Hospital, Lianyungang, Jiangsu 222000, P.R. China, Department of Biomedical Science, CHA University, Gyeonggi 13488, Republic of Korea
    Copyright: © Pei et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 25
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    Published online on: November 3, 2025
       https://doi.org/10.3892/mmr.2025.13735
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Abstract

Preeclampsia (PE) is a multifactorial pregnancy disorder characterized by hypertension and proteinuria, primarily resulting from placental abnormalities and endothelial dysfunction. The present review explores the role of ubiquitination and deubiquitination (key post‑translational modifications), in the pathogenesis of PE. Ubiquitination, catalyzed by E1, E2 and E3 enzymes, and reversed by deubiquitinating enzymes, regulates protein stability and function, thereby influencing key cellular processes in trophoblasts. Dysregulation of these pathways impairs trophoblast functions and contributes to PE development. In addition, the present review discusses emerging therapeutic strategies targeting the ubiquitin‑proteasome system, including deubiquitinase‑targeting chimera and proteolysis‑targeting chimeras. Targeting ubiquitination and deubiquitination mechanisms presents a promising avenue for the treatment of PE. Further research into these pathways may lead to novel interventions aimed at improving maternal and fetal outcomes.
View Figures

Figure 1

Principles of ubiquitination and
deubiquitinating enzymes in the ubiquitin-proteasome system. During
the ubiquitination process, Ub is conjugated to the substrate
through the actions of E1, E2 and E3 enzymes. During the
deubiquitination process, DUBs remove ubiquitin from the substrate.
The substrate labeled with ubiquitin is then recognized and
degraded by the 26S proteasome, resulting in protein degradation
products. Ub, ubiquitin; DUBs, deubiquitinating enzymes.

Figure 2

Mechanistic diagram of ubiquitinating
enzymes in preeclampsia. COP1 promotes the degradation of p57,
thereby impairing trophoblast fusion. The ASB4 targets ID2 for
degradation, inhibiting angiogenesis. Silencing THBS1 enhances the
NEDD4-mediated ubiquitination and degradation of TAK1, which
suppresses trophoblast fusion, proliferation, migration and
invasion, while increasing the cell cycle arrest and apoptosis.
NEDD4L adds ubiquitin to ENaC, promoting its degradation or
altering its function. miRNA-218-5p upregulates the UBE3A
expression, which facilitates the degradation of SATB1, thereby
inhibiting trophoblast migration, invasion and ER/oxidative stress.
Cb1 promotes MET degradation, reducing trophoblast invasion. TRIM72
facilitates p53 degradation, suppressing apoptosis and enhancing
proliferation and migration. The upregulation of RNF by CCNG2
promotes Dvl12 degradation, suppressing EMT markers and MMP
expression via the Wnt/PCP pathway, thereby reducing cell invasion.
β-TrCP1 degrades Snail and VEGFRs, blocking EMT and angiogenesis.
FBW2 degrades GCM1, disrupting the EMT processes. The
downregulation of LncRNA-DUXAP8 enhances PCBP2 ubiquitination and
degradation, which activates the Akt/mTOR signaling pathway. This
activation decreases FAM134B, a known inhibitor of cell
proliferation, invasion, migration and ER stress. Hypoxia reduces
FUNDC1 ubiquitination, which promotes trophoblast autophagy. Akt
phosphorylates STOX1, influencing its ubiquitination and stability,
and modulating trophoblast invasion and proliferation. miRNA,
microRNA; ER, endoplasmic reticulum; GCM1, glial cells missing
transcription factor 1; FBW2, F-box and wd repeat domain containing
2; STK40, serine/threonine kinase 40; COP1, constitutively
photomorphogenic 1; ASB4, ankyrin repeat and SOCS box containing 4;
ID2, inhibitor of DNA binding 2; Trcp1, transient receptor
potential cation channel subfamily C member 1; SATB1, special
AT-rich sequence binding-protein 1; UBE3A, ubiquitin-protein ligase
E3A; THSB1, thrombospondin 1; NEDD4, neural precursor cell
expressed developmentally downregulated 4; TAK1, TGF-β-activated
kinase 1; FUNDC1, FUN14 domain-containing protein 1; GSH,
glutathione; SOD, superoxide dismutase; ROS, reactive oxygen
species; MDA, malondialdehyde; TRIM72, tripartite motif containing
72; FAM124B, family with sequence similarity 124 member B; LC2II,
microtubule-associated protein 1 light chain 3-II; MEK,
mitogen-activated protein kinase kinase; HGF, hepatocyte growth
factor; MET, mesenchymal-epithelial transition factor; Cbl, casitas
B-lineage lymphoma; RNF123, ring finger protein 123; Dvl2,
dishevelled segment polarity protein 2; PCP, planar cell polarity;
CCNG2, cyclin G2; ENaC, epithelial sodium channel; CAV1, caveolin
1; PCBP2, poly (rC)-binding protein 2; MT, mitochondria.

Figure 3

Mechanistic diagram of DUBs in
preeclampsia. USP22 stabilizes ADAM9, inhibiting cell
proliferation, migration, invasion and EMT through the
Wnt/β-catenin signaling pathway. USP14 stabilizes NF-κB and HAND1,
promoting proinflammatory factors and affecting estrogen synthesis.
USP14 also stabilizes PFN1, contributing to vascular endothelial
injury via the Rho/ROCK-signaling pathway. USP8 stabilizes ENaC,
inhibiting cell invasion, migration and proliferation. USP17
stabilizes HDAC2, activating STAT1 and enhancing the secretion of
proinflammatory factors. USP, ubiquitin-specific protease; ENaC,
epithelial sodium channel; EMT, epithelial-mesenchymal transition;
ROS, reactive oxygen species; HAND1, heart and neural crest
derivatives expressed 1; PFN1, penetration 1; RGS2, regulator of
G-protein signaling 2.
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Copy and paste a formatted citation
Spandidos Publications style
Pei C, Song X, Xu H and Baek K: Role of ubiquitin‑proteasome system in preeclampsia (Review). Mol Med Rep 33: 25, 2026.
APA
Pei, C., Song, X., Xu, H., & Baek, K. (2026). Role of ubiquitin‑proteasome system in preeclampsia (Review). Molecular Medicine Reports, 33, 25. https://doi.org/10.3892/mmr.2025.13735
MLA
Pei, C., Song, X., Xu, H., Baek, K."Role of ubiquitin‑proteasome system in preeclampsia (Review)". Molecular Medicine Reports 33.1 (2026): 25.
Chicago
Pei, C., Song, X., Xu, H., Baek, K."Role of ubiquitin‑proteasome system in preeclampsia (Review)". Molecular Medicine Reports 33, no. 1 (2026): 25. https://doi.org/10.3892/mmr.2025.13735
Copy and paste a formatted citation
x
Spandidos Publications style
Pei C, Song X, Xu H and Baek K: Role of ubiquitin‑proteasome system in preeclampsia (Review). Mol Med Rep 33: 25, 2026.
APA
Pei, C., Song, X., Xu, H., & Baek, K. (2026). Role of ubiquitin‑proteasome system in preeclampsia (Review). Molecular Medicine Reports, 33, 25. https://doi.org/10.3892/mmr.2025.13735
MLA
Pei, C., Song, X., Xu, H., Baek, K."Role of ubiquitin‑proteasome system in preeclampsia (Review)". Molecular Medicine Reports 33.1 (2026): 25.
Chicago
Pei, C., Song, X., Xu, H., Baek, K."Role of ubiquitin‑proteasome system in preeclampsia (Review)". Molecular Medicine Reports 33, no. 1 (2026): 25. https://doi.org/10.3892/mmr.2025.13735
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