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How transcription factors regulate apoptosis in endometriosis (Review)

  • Authors:
    • Zhuqing Ouyang
    • Juexiao Deng
    • Lanyue Zhang
    • Fujin Shen
  • View Affiliations / Copyright

    Affiliations: Department of Gynaecology and Obstetrics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
    Copyright: © Ouyang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 289
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    Published online on: August 18, 2025
       https://doi.org/10.3892/mmr.2025.13654
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Abstract

Endometriosis (EM) is a common chronic gynaecological disease that affects 10% of women of reproductive age globally. EM is defined as the presence of endometrial glands and stroma in extrauterine locations, and it can result in pelvic pain and infertility. Inflammation, oxidative stress and apoptosis dysregulation serve a key role in endometriotic lesions. The pathogenesis of EM remains unclear, posing major clinical challenges in its diagnosis and treatment. Apoptosis contributes to the maintenance of cellular homeostasis during the menstrual cycle by eliminating ageing cells from the functional layer of the uterine endometrium. Inhibition of apoptosis facilitates ectopic endometrial cell invasion, implantation and survival, and it promotes the occurrence and development of EM. Transcription factors are pivotal regulators of cellular processes and serve key roles in regulating apoptosis to promote EM. Therefore, identifying the mechanisms by which transcription factors regulate apoptosis in EM may help identify novel targets for the treatment of this disease. The present review summarizes the regulation of apoptosis by different transcription factors in the pathogenesis of EM, contributing to the development of promising biomarkers and therapeutic strategies.
View Figures

Figure 1

Accumulation of ROS in the lesion
area of patients with endometriosis triggers Ca2+
release through the activation of TRPML1 on lysosomes. This
Ca2+ release promotes the dephosphorylation and nuclear
translocation of TFEB, facilitating the transcription of certain
target genes, such as ATG5, Beclin1, LC3b, P62 and Bcl-2.
Upregulated ATG5 directly interacts with and inhibits FADD, which
suppresses procaspase-8 cleavage, ultimately inhibiting the caspase
cascade and apoptosis. Similarly, upregulated Beclin1 inhibits the
tBid-mediated activation of Bax/Bak on mitochondria, preventing Cyt
c efflux and endogenous apoptosis. LC3 binds to the P62
protein and promotes P62 degradation. The degradation of P62
prevents the phosphorylation and degradation of Fap-1. Thus, P62
degradation directly inhibits endogenous apoptosis and indirectly
suppresses apoptosis via its regulation of Fap-1. ROS, reactive
oxygen species; TRPML1, transient receptor potential mucolipin 1;
Lys, lysosome; TFEB, transcription factor EB; P, phosphorylated;
ATG5, autophagy related 5; FADD, Fas-associated death domain
protein; DR4/5, death receptor 4/5; Fap-1, familial adenomatous
polyposis-1; Cyt c, cytochrome c; tBid, truncated BH3
interacting-domain death agonist; Bak, Bcl-2 homologous antagonist
killer.

Figure 2

NF-κB is activated in patients with
EM via classical and alternative pathways. The classical pathway
involves the activation of TNF-α by LTBP2 upregulation in the serum
of patients with EM and ectopic endometrial tissue. TNF-α mediates
the activation of the IKK complex to promote the phosphorylation
and proteolytic degradation of IκB, ultimately leading to the
activation of NF-κB and its translocation to the nucleus. The
alternative pathway is initiated by low KLF10 expression in the
ectopic endometria of patients with EM, which activates CD40. CD40
mediates NIK activation and the sequential activation of IKKα.
Activated IKKα induces phosphorylation and partial hydrolysis of
the P100 protein in the P100-Rel B dimer to form the
transcriptionally active P52-Rel B dimer, which then migrates
towards the nucleus. Once in the nucleus, NF-κB promotes the
expression of target genes, such as XIAP, Bcl-2 and Bcl-xl, which
inhibit the activation of Bax/Bak and suppresses Cyt c
release, thereby preventing apoptosis. Furthermore, NF-κB nuclear
translocation inhibits the function of the P53 tumour suppressor
protein. This suppression reduces the expression of proapoptotic
genes, such as Puma, Noxa and Bax, which are involved in
Bax-/Bak-mediated Cyt c release and apoptosis. P53 also
directly promotes the expression of DR4/5, Fas and its ligand
(Fasl) on cell membranes, initiating exogenous apoptosis. By
inhibiting P53 activity, NF-κB indirectly contributes to the
suppression of both endogenous and exogenous apoptosis pathways.
EM, endometriosis; LTBP2, latent transforming growth factor β
binding protein 2; TNFR, TNF receptor; P, phosphorylated; KLF10,
Krüppel-like factor 10; NIK, NF-κB-inducing kinase; XIAP, X-linked
inhibitor of apoptosis; Cyt c, cytochrome c; Puma,
P53 upregulated modulator of apoptosis; Noxa, a BH3-only
proapoptosis protein; FADD, Fas-associated death domain protein;
Fasl, Fas ligand; Bak, Bcl-2 homologous antagonist killer; DR4/5,
death receptor 4/5.

Figure 3

CREB/P300 is expressed at low levels
in EM, but CREB/P300 binds to FOXO1 to promote its acetylation and
activate the regulatory effects of FOXO1 on its target genes, such
as Fas, Bim and TRAIL. Bim triggers Bax/Bak activation, leading to
Cyt c release and the initiation of endogenous apoptosis.
Additionally, increased expression of Fas and TRAIL enhances
caspase-8 production, activating the caspase cascade and inducing
exogenous apoptosis. Conversely, patients with EM exhibit high
expression levels of SIRT1, which facilitates FOXO1 deacetylation
and inhibits FOXO1 activation, thus preventing the initiation of
apoptosis. Furthermore, increased expression levels of NEK2 and AKT
in patients with EM promote FOXO1 phosphorylation. Phosphorylated
FOXO1 binds to the 14-3-3 protein and translocates out of the
nucleus, which inhibits the regulatory effect of FOXO1 on target
genes in the nucleus and inhibits apoptosis. EM, endometriosis;
CREB, cAMP response element-binding protein; Bim, Bcl-2 interacting
mediator of cell death; TRAIL, TNF-related apoptosis-inducing
ligand; Cyt c, cytochrome c; SIRT1, sirtuin 1; NEK,
NIMA-related kinase; DR4/5, death receptor 4/5; FADD,
Fas-associated death domain protein; Fasl, Fas ligand; Bak, Bcl-2
homologous antagonist killer; P, phosphorylated; ac,
acetylated.
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Copy and paste a formatted citation
Spandidos Publications style
Ouyang Z, Deng J, Zhang L and Shen F: How transcription factors regulate apoptosis in endometriosis (Review). Mol Med Rep 32: 289, 2025.
APA
Ouyang, Z., Deng, J., Zhang, L., & Shen, F. (2025). How transcription factors regulate apoptosis in endometriosis (Review). Molecular Medicine Reports, 32, 289. https://doi.org/10.3892/mmr.2025.13654
MLA
Ouyang, Z., Deng, J., Zhang, L., Shen, F."How transcription factors regulate apoptosis in endometriosis (Review)". Molecular Medicine Reports 32.5 (2025): 289.
Chicago
Ouyang, Z., Deng, J., Zhang, L., Shen, F."How transcription factors regulate apoptosis in endometriosis (Review)". Molecular Medicine Reports 32, no. 5 (2025): 289. https://doi.org/10.3892/mmr.2025.13654
Copy and paste a formatted citation
x
Spandidos Publications style
Ouyang Z, Deng J, Zhang L and Shen F: How transcription factors regulate apoptosis in endometriosis (Review). Mol Med Rep 32: 289, 2025.
APA
Ouyang, Z., Deng, J., Zhang, L., & Shen, F. (2025). How transcription factors regulate apoptosis in endometriosis (Review). Molecular Medicine Reports, 32, 289. https://doi.org/10.3892/mmr.2025.13654
MLA
Ouyang, Z., Deng, J., Zhang, L., Shen, F."How transcription factors regulate apoptosis in endometriosis (Review)". Molecular Medicine Reports 32.5 (2025): 289.
Chicago
Ouyang, Z., Deng, J., Zhang, L., Shen, F."How transcription factors regulate apoptosis in endometriosis (Review)". Molecular Medicine Reports 32, no. 5 (2025): 289. https://doi.org/10.3892/mmr.2025.13654
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