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Mechanistic insights into inflammatory cytokines in adenomyosis‑induced infertility (Review)

  • Authors:
    • Bojiao Yang
    • Feng Li
    • Guimao Cao
    • Mingtu Nuo
    • Yaxin Shi
    • Zilu Wang
    • Jing Jia
    • Wei Shi
    • Zhiyong Liu
  • View Affiliations / Copyright

    Affiliations: First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250014, P.R. China, Department of Anesthesiology, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250011, P.R. China, Department of Reproductive Medicine, Inner Mongolia Maternal and Child Health Care Hospital, Hohhot, Inner Mongolia Autonomous Region 010020, P.R. China, Department of Gynecology, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250014, P.R. China, Central Laboratory, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250014, P.R. China
    Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 107
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    Published online on: March 2, 2026
       https://doi.org/10.3892/ijmm.2026.5778
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Abstract

Adenomyosis (AM), an estrogen‑dependent chronic inflammatory disease with a rising incidence, has emerged as a major cause of infertility and reduced clinical pregnancy rates in reproductive‑aged women, severely impairing reproductive health and quality of life. The core pathological mechanisms of AM are closely linked to aberrant local expression of inflammatory cytokines, including interleukin (IL)‑6, C‑X‑C motif chemokine ligand 8 (CXCL8), IL1B, tumor necrosis factor‑α, NF‑κB, cyclooxygenase‑2 and TGF‑β, which disrupt the immune barrier at the endometrial‑myometrial junction. This disruption further breaks the critical balance between proinflammatory and anti‑inflammatory cytokines, ultimately fostering an immune microenvironment hostile to embryo survival. Concurrently, inflammatory cytokine‑activated cellular processes, including proliferation, invasion, tissue injury and repair, epithelial‑mesenchymal transition and fibrosis, further induce pathological neovascularization and impair blood perfusion in the junctional zone. These pathological changes, in turn, compromise endometrial receptivity and inhibit decidualization, ultimately resulting in implantation failure. Based on these mechanisms, key inflammatory cytokines such as IL‑6, CXCL8, IL1B and IL‑10 hold potential as diagnostic biomarkers for AM‑related infertility and provide a theoretical basis for developing fertility‑preserving therapies targeting the inflammatory cascade (such as IL‑6 receptor monoclonal antibodies and TGF‑β inhibitors). These findings offer new approaches to achieve the dual goals of lesion control and fertility preservation in clinical practice.
View Figures

Figure 1

Main inflammatory pathways through
which inflammatory cytokines promote the occurrence and development
of adenomyosis. IL-1, IL-6, CXCL8 and IL10 are the inflammatory
cytokines mainly described in the present review. Their promotion
of the establishment and development of adenomyosis mainly involves
signal pathways such as JAK/STAT, PI3K/AKT/mTOR, RAS/RAF/MEK/ERK
and NK-κB. AKT, protein kinase B; CXCR1/2, C-X-C chemokine receptor
1/2; ERK, extracellular signal-regulated kinase; FAK, focal
adhesion kinase; gp130, glycoprotein 130; IKKa/b, IκB kinase a/b;
IκBa, inhibitor of nuclear factor κB a; IL, interleukin; IL-1R1,
interleukin-1 receptor 1; IL-1Rap, interleukin-1 receptor accessory
protein; IRAK, interleukin-1 receptor-associated kinase; JAK, Janus
kinase; MAPK, mitogen-activated protein kinase; MEK,
mitogen-activated protein kinase kinase; mTOR, mammalian target of
rapamycin; MyD88, myeloid differentiation primary response 88;
NF-κB, nuclear factor κ-light-chain-enhancer of activated B Cells;
PI3K, phosphatidylinositol 3-kinase; RAF, rapidly accelerated
fibrosarcoma; RAS, rat sarcoma viral oncogene homolog; STAT3,
signal transducer and activator of transcription 3; TIR,
Toll/interleukin-1 receptor domain.

Figure 2

Abnormal aggregation of inflammatory
cytokines affects the inflammatory microenvironment and interferes
with multiple stages of embryo implantation. Tissue damage at the
endometrium-myometrium interface is the key trigger for abnormal
aggregation of inflammatory cytokines. Among them, IL-6, CXCL8,
VEGF, IL10, COX-2, IL1B and MCP-1 are upregulated, while LIF,
HOXA10, HOXA11, IGβ3, OPN, IL11, HIF-2α and IHH are downregulated.
The abnormal inflammatory microenvironment leads to
hyperperistalsis of the uterus, decreased fallopian tube transport
function, abnormal placental formation and decreased endometrial
receptivity. COX-2, cyclooxygenase-2; HIF-2α, Hypoxia-Inducible
Factor-2α; HOXA10, homeobox A10; HOXA11, homeobox A11; IHH, Indian
hedgehog; IGβ3, integrin β3; IL, interleukin; LIF, leukemia
inhibitory factor; MCP-1, monocyte chemoattractant protein-1; OPN,
osteopontin; VEGF, vascular endothelial growth factor.

Figure 3

Overview of interactions between
inflammatory cytokines in adenomyosis-related infertility in the
present review. However, these interactions do not necessarily
represent the actual or complete biological pathways. NF-κB,
nuclear factor κB; HIF1A, hypoxia-inducible factor 1α; VEGF,
vascular endothelial growth factor; TGF-β, transforming growth
factor β; MMP, matrix metalloproteinase; HLA-G, human leucocyte
antigen-G; COX2, cyclooxygenase2; PGE2, prostaglandin E2; TF,
tissue factor; BMP-2, bone morphogenetic protein-2; CEBPE,
CCAAT/enhancer-binding protein ε; EMT, epithelial-mesenchymal
transition; FMT, fibroblast-myofibroblast transition; FOXO1,
forkhead box O1; HAND2, heart and Neural Crest Derivatives
Expressed 2; HOXA10, homeobox A10; HOXA11, homeobox A11; IHH,
Indian hedgehog; IL, interleukin; JAK, Janus kinase; KLF5,
Kruppel-like factor 5; LIF, leukemia inhibitory factor; NK cells,
natural killer cells; gp130, glycoprotein 130; SMM, smooth muscle
metaplasia; STAT, signal transducer and activator of transcription;
TIAR, tissue injury and repair; Tregs, regulatory T cells.

Figure 4

Main process of angiogenesis. First,
endometrial bleeding occurs periodically as a sign of tissue
damage. Second, platelet adhesion and aggregation participate in
hemostasis. Third, platelets attract inflammatory cytokines and
immune cells to gather at the wound. Fourth, inflammatory cytokines
act as angiogenic factors to induce neovascularization of ectopic
endometrium and upregulate factors directly related to angiogenesis
such as VEGF, FGF and PDGF. Among them, hypoxia is a crucial
inducing factor. Fifth, abnormal angiogenesis leads to decreased
endometrial receptivity and affects embryo implantation. EC,
endothelial cell; FGF, fibroblast growth factor; PDGF,
platelet-derived growth factor; VEGF, vascular endothelial growth
factor.

Figure 5

Main pathogenesis of
adenomyosis-related female infertility. Inflammatory cytokines
mainly promote the occurrence and development of adenomyosis by
promoting TIAR and EMT and interfere with the normal embryo
implantation process by promoting angiogenesis, leading to
decreased endometrial receptivity and impaired decidualization.
BMP-2, bone morphogenetic protein-2; CEBPB, CCAAT/enhancer-binding
protein β; COX-2, cyclooxygenase-2; E2, estradiol; EMT,
epithelial-mesenchymal transition; ERα, Estrogen Receptor Alpha;
ERβ, Estrogen Receptor β; FAK, Focal Adhesion Kinase; FOXO1,
Forkhead Box O1; HIF-1α, hypoxia-inducible factor-1α; Hox-A10/A11,
homeobox A10/A11; IL, interleukin; JAK2, Janus kinase 2; KLF5,
Kruppel-like factor 5; LIF, leukemia inhibitory factor; MMP, matrix
metalloproteinase; OPN, osteopontin; PGE2, prostaglandin E2; STAR,
steroidogenic acute regulatory protein; TGF-β, transforming growth
factor-β; TIAR, tissue injury and repair; uNK cells, uterine
natural killer cells; VEGF, vascular endothelial growth factor.

Figure 6

Main therapeutic strategies for
adenomyosis-related female infertility. Taking inflammatory
cytokines as the core regulatory target, this figure covers
multiple therapeutic modalities including NSAIDs, hormonal therapy,
interleukin-targeted therapies, immunomodulators, TCM and emerging
therapeutic technologies and displays the corresponding specific
drugs and their action targets for each modality. These therapeutic
strategies can modulate inflammatory cytokines, thereby
ameliorating adenomyosis-associated pathological processes, further
enhancing endometrial receptivity and reversing decidualization
dysfunction, which contributes to improving the infertility
outcomes in women with adenomyosis. TCM, Traditional Chinese
Medicine; GnRH-a, gonadotropin-releasing hormone agonist; GnRH-A,
gonadotropin-releasing hormone antagonist; IKKβ, IκB kinase β; IL,
interleukin; MCP-1, monocyte chemoattractant protein-1; NSAIDs,
non-steroidal anti-inflammatory drugs; PR, progesterone
receptor.
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Spandidos Publications style
Yang B, Li F, Cao G, Nuo M, Shi Y, Wang Z, Jia J, Shi W and Liu Z: Mechanistic insights into inflammatory cytokines in adenomyosis‑induced infertility (Review). Int J Mol Med 57: 107, 2026.
APA
Yang, B., Li, F., Cao, G., Nuo, M., Shi, Y., Wang, Z. ... Liu, Z. (2026). Mechanistic insights into inflammatory cytokines in adenomyosis‑induced infertility (Review). International Journal of Molecular Medicine, 57, 107. https://doi.org/10.3892/ijmm.2026.5778
MLA
Yang, B., Li, F., Cao, G., Nuo, M., Shi, Y., Wang, Z., Jia, J., Shi, W., Liu, Z."Mechanistic insights into inflammatory cytokines in adenomyosis‑induced infertility (Review)". International Journal of Molecular Medicine 57.5 (2026): 107.
Chicago
Yang, B., Li, F., Cao, G., Nuo, M., Shi, Y., Wang, Z., Jia, J., Shi, W., Liu, Z."Mechanistic insights into inflammatory cytokines in adenomyosis‑induced infertility (Review)". International Journal of Molecular Medicine 57, no. 5 (2026): 107. https://doi.org/10.3892/ijmm.2026.5778
Copy and paste a formatted citation
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Spandidos Publications style
Yang B, Li F, Cao G, Nuo M, Shi Y, Wang Z, Jia J, Shi W and Liu Z: Mechanistic insights into inflammatory cytokines in adenomyosis‑induced infertility (Review). Int J Mol Med 57: 107, 2026.
APA
Yang, B., Li, F., Cao, G., Nuo, M., Shi, Y., Wang, Z. ... Liu, Z. (2026). Mechanistic insights into inflammatory cytokines in adenomyosis‑induced infertility (Review). International Journal of Molecular Medicine, 57, 107. https://doi.org/10.3892/ijmm.2026.5778
MLA
Yang, B., Li, F., Cao, G., Nuo, M., Shi, Y., Wang, Z., Jia, J., Shi, W., Liu, Z."Mechanistic insights into inflammatory cytokines in adenomyosis‑induced infertility (Review)". International Journal of Molecular Medicine 57.5 (2026): 107.
Chicago
Yang, B., Li, F., Cao, G., Nuo, M., Shi, Y., Wang, Z., Jia, J., Shi, W., Liu, Z."Mechanistic insights into inflammatory cytokines in adenomyosis‑induced infertility (Review)". International Journal of Molecular Medicine 57, no. 5 (2026): 107. https://doi.org/10.3892/ijmm.2026.5778
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