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

Authors

Qianru Dou, Zhengjie Han, Wenxiao Shao, Yongli Liu, Shenghui Yao, Yingying Qiu

Published in

Journal of nanobiotechnology. Jul 18, 2026. Epub Jul 18, 2026.

Abstract

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.
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.
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.
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.

PMID:
42471623
Bibliographic data and abstract were imported from PubMed on 19 Jul 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.