Inactivation of the leukemia inhibitory factor/signal transducer and activator of transcription 3 pathway: a pivotal mechanism in adenomyosis-related embryo implantation failure

Dou Q, Qianru Dou, Zhengjie Han, Han Z, Shao W, Wenxiao Shao, Liu Y, Yongli Liu, Yao S, Shenghui Yao, Yingying Qiu, Qiu Y
Journal of nanobiotechnology · 2026 · vol. 24(1) · doi:10.1186/s12951-026-04505-z · PMID:42471623 · PMC13663250 · W7169684109
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The LIF/STAT3 pathway is inactivated in adenomyosis patients due to inflammation and metabolic issues, leading to implantation failure, which a nanotherapeutic strategy successfully reversed in an experimental model.

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This study investigates the molecular mechanisms linking adenomyosis to embryo implantation failure, focusing on the downregulation of the leukemia inhibitory factor and signal transducer and activator of transcription 3 signaling pathway. Analysis of clinical endometrial samples and a three-dimensional co-culture system revealed that pathologically elevated inflammatory cytokines suppress this pathway via NF-κB activation, while metabolomic profiling associates its inactivation with aberrant cellular energy metabolism. The researchers developed a tofacitinib-loaded biomimetic nanogel that successfully mitigated local inflammation, reactivated the signaling pathway, and improved embryo implantation rates in experimental models. This paper is centrally about adenomyosis — specifically addressing its role in compromised embryo implantation through inflammatory and metabolic dysregulation of endometrial receptivity.

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Abstract

BACKGROUND: Adenomyosis (AM) is frequently associated with compromised embryo implantation. The leukemia inhibitory factor (LIF)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is crucial for endometrial receptivity; however, its mechanistic role in AM-related implantation failure remains insufficiently elucidated. This study aimed to investigate the inactivation mechanism of the LIF/STAT3 pathway in AM and to evaluate a novel nanotherapeutic strategy for restoring implantation capacity. METHODS: Clinical endometrial samples from AM patients and controls were analyzed. A three-dimensional (3D) co-culture system simulating the endometrial microenvironment was established. Interventions were performed using a tofacitinib-loaded biomimetic nanogel (Tofa-NG). Comprehensive analyses included bulk RNA Sequencing (RNA-seq), immunohistochemistry (IHC), RT-qPCR, proteomics, inflammatory cytokine profiling, and metabolomics to dissect the pathological links. RESULTS: The LIF/STAT3 signaling pathway was significantly downregulated in the endometrium of AM patients, correlating directly with implantation failure. Pathologically elevated inflammatory cytokines suppressed LIF expression via NF-κB pathway activation, exacerbating the inflammatory microenvironment. Metabolomic profiling revealed a strong association between LIF/STAT3 pathway inactivation and aberrant cellular energy metabolism. The engineered Tofa-NG facilitated targeted drug delivery, effectively mitigated local inflammation, and successfully reactivated the LIF/STAT3 pathway. Consequently, this intervention significantly improved the embryo implantation success rate in the experimental model. CONCLUSION: This study identifies the inactivation of the LIF/STAT3 pathway as a central mechanism underlying embryo implantation defects in AM, intricately linked to chronic inflammation and metabolic dysregulation. The Tofa-NG strategy demonstrates promising therapeutic potential by rectifying the signaling deficit and ameliorating the endometrial microenvironment. These findings provide a novel theoretical foundation for developing targeted, personalized treatments for infertility associated with AM.
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Abstract

Background Adenomyosis (AM) is frequently associated with compromised embryo implantation. The leukemia inhibitory factor (LIF)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is crucial for endometrial receptivity; however, its mechanistic role in AM-related implantation failure remains insufficiently elucidated. This study aimed to investigate the inactivation mechanism of the LIF/STAT3 pathway in AM and to evaluate a novel nanotherapeutic strategy for restoring implantation capacity.

Methods

Clinical endometrial samples from AM patients and controls were analyzed. A three-dimensional (3D) co-culture system simulating the endometrial microenvironment was established. Interventions were performed using a tofacitinib-loaded biomimetic nanogel (Tofa-NG). Comprehensive analyses included bulk RNA Sequencing (RNA-seq), immunohistochemistry (IHC), RT-qPCR, proteomics, inflammatory cytokine profiling, and metabolomics to dissect the pathological links.

Results

The LIF/STAT3 signaling pathway was significantly downregulated in the endometrium of AM patients, correlating directly with implantation failure. Pathologically elevated inflammatory cytokines suppressed LIF expression via NF-κB pathway activation, exacerbating the inflammatory microenvironment. Metabolomic profiling revealed a strong association between LIF/STAT3 pathway inactivation and aberrant cellular energy metabolism. The engineered Tofa-NG facilitated targeted drug delivery, effectively mitigated local inflammation, and successfully reactivated the LIF/STAT3 pathway. Consequently, this intervention significantly improved the embryo implantation success rate in the experimental model.

Conclusion

This study identifies the inactivation of the LIF/STAT3 pathway as a central mechanism underlying embryo implantation defects in AM, intricately linked to chronic inflammation and metabolic dysregulation. The Tofa-NG strategy demonstrates promising therapeutic potential by rectifying the signaling deficit and ameliorating the endometrial microenvironment. These findings provide a novel theoretical foundation for developing targeted, personalized treatments for infertility associated with AM. Graphical abstract Similar content being viewed by others Abbreviations - AM: - Adenomyosis - ANOVA: - Analysis of variance - ATP: - Adenosine triphosphate - BSA: - Bovine serum albumin - BP: - Biological processes - CC: - Cellular components - CS: - Chitosan - DEGs: - Differentially expressed genes - DEPs: - Differentially expressed proteins - DHE: - Dihydroethidium - ECM: - Extracellular matrix - EECs: - Endometrial epithelial cells - FDR: - False discovery rate - GO: - Gene ontology - GSEA: - Gene set enrichment analysis - HESC: - Human endometrial stromal cell - H&E: - Hematoxylin and eosin - iBAQ: - Intensity-based absolute quantification - IHC: - Immunohistochemistry - KEGG: - Kyoto encyclopedia of genes and genomes - LC-MS/MS: - Liquid chromatography-tandem mass spectrometry - LFQ: - Label-free quantification - LIF: - Leukemia inhibitory factor - m6A: - N6-Methyladenosine - MeRIP-qPCR: - Methylated RNA immunoprecipitation followed by quantitative polymerase chain reaction - MF: - Molecular functions - NES: - Normalized enrichment scores - NGF: - Nerve growth factor - PAA: - Polyacrylic acid - PCA: - Principal component analysis - PBS: - Phosphate-buffered saline - PLS-DA: - Partial least squares discriminant analysis - RIP-qPCR: - RNA immunoprecipitation followed by quantitative polymerase chain reaction - RNA-seq: - RNA sequencing - ROS: - Reactive oxygen species - SMPDB: - Small molecule pathway database - STAT3: - Signal transducer and activator of transcription 3 - TLR4: - Toll-like receptor 4 - Tofa: - Tofacitinib - Tofa-NG: - Tofacitinib-loaded biomimetic nanogel - VAS: - Visual analogue scale - VIP: - Variable importance in projection - WB: - Western blot - Δψm: - Mitochondrial membrane potential - 2D: - Two-dimensional - 3D: - Three-dimensional

Acknowledgements

None. Funding Funded by Science and Technology Program of Xuzhou (Grant No. KC25074), and Science and Technology Project of Jiangsu Provincial Administration of Traditional Chinese Medicine (Grant No. MS2023079), and “Jinding” Reserve Talents Project of the Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University (Grant No. XYYJDYCHB202501). Author information Authors and Affiliations Corresponding author Ethics declarations Ethics approval and consent to participate 1. This study was approved by the Medical Ethics Committee of the Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University (Approval No. Xyyll [2025] 167). All patients included in the study provided informed consent. 2. All the animal experiments were approved by the Animal Experiment Ethics Committee of the Jiangsu Provincial Hospital of Integrated Traditional Chinese and Western Medicine (AEWC-20241009443). Consent for publication All authors agree to publish the article. Competing interests The authors declare no competing interests. Additional information Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary Information Rights and permissions Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. About this article Cite this article Dou, Q., Han, Z., Shao, W. et al. Inactivation of the leukemia inhibitory factor/signal transducer and activator of transcription 3 pathway: a pivotal mechanism in adenomyosis-related embryo implantation failure. J Nanobiotechnol (2026). https://doi.org/10.1186/s12951-026-04505-z Received: Accepted: Published: DOI: https://doi.org/10.1186/s12951-026-04505-z

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MeSH descriptors

Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Embryo Implantation Embryo Implantation Embryo Implantation Embryo Implantation Embryo Implantation Embryo Implantation Embryo Implantation Embryo Implantation Leukemia Inhibitory Factor Leukemia Inhibitory Factor Leukemia Inhibitory Factor Leukemia Inhibitory Factor

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