Targeting E-Selectin and ICAM1 Suppresses Endometriosis Progression by Disrupting the Inflammation–Fibrosis Axis and Reducing Local M2 Macrophage Infiltration

Endometriosis is a chronic inflammatory disease driven by progressive fibrosis, yet the functional roles of adhesion molecules E-selectin and ICAM1 in mediating the inflammation–fibrosis axis remain poorly defined. This study aimed to investigate whether pharmacological inhibition of E-selectin and ICAM1 can attenuate inflammation and fibrosis in endometriosis. Human endometrial tissues (28 normal, 28 eutopic, 32 ectopic) were assessed for E-selectin and ICAM1 protein expression by immunohistochemistry on tissue microarrays. A murine endometriosis model was established in female C57BL/6 J mice, which were treated with A-205804 (an orally bioavailable dual inhibitor of E-selectin and ICAM1, 10 mg/kg) or vehicle for 2 weeks. Lesion volume and weight, fibrosis markers (Masson staining, α-SMA immunohistochemistry), cytokine profiling (Olink proteomics), bulk RNA sequencing, and single-cell RNA sequencing were performed to evaluate treatment effects and underlying mechanisms. E-selectin and ICAM1 were significantly upregulated in ectopic endometrium compared to normal and eutopic endometrium. A-205804 treatment reduced lesion volume and weight, decreased collagen deposition and α-SMA expression, and downregulated pathways related to NF-κB signaling, TNF signaling, and chemokine signaling. Pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, CCL2) and pro-fibrotic factors (TGF-β1, IL-10) were markedly reduced at both the mRNA and protein levels. Single-cell RNA sequencing revealed a lower proportion of M2 macrophages in treated lesions; however, formal between-group statistical comparison was not possible because only one pooled sample was analyzed per group. Furthermore, TNF-α-induced lesion growth and E-selectin/ICAM1 upregulation were reversed by A-205804 co-treatment in vivo. These findings suggest that inhibition of E-selectin and ICAM1 attenuates endometriotic lesion progression in mice by suppressing macrophage-mediated inflammation and disrupting the TNF-α/E-selectin/ICAM1 positive feedback loop. Abbreviations - CCL2: - C-C motif chemokine ligand 2 - FDR: - False discovery rate - GSVA: - Gene set variation analysis - HE: - Hematoxylin-eosin - ICAM1: - Intercellular adhesion molecule 1 - IHC: - Immunohistochemistry - KEGG: - Kyoto Encyclopedia of Genes and Genomes - LFA-1: - Lymphocyte function-associated antigen 1 - MSigDB: - Molecular Signatures Database - NF-κB: - Nuclear factor kappa B - NK: - Natural killer - NPX: - Normalized protein expression - PBS: - Phosphate-buffered saline - PCA: - Principal component analysis - PSGL-1: - P-selectin glycoprotein ligand-1 - rASRM: - Revised American Society for Reproductive Medicine - SD: - Standard deviation - TGF-β1: - Transforming growth factor beta 1 - TNF-α: - Tumor necrosis factor alpha - UMAP: - Uniform manifold approximation and projection - α-SMA: - Alpha-smooth muscle actin

Not applicable. Funding This work was supported by the Medical and Health Science Program of Zhejiang Province (Grant No. 2025HY0617), the Funds of the Natural Science Foundation of Hangzhou (Grant No. 2025SZRJJ0477), and the Construction Fund of Key Medical Disciplines of Hangzhou (Grant No. 2025HZZD07). Author information Authors and Affiliations Corresponding authors Ethics declarations Ethics Approval The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of Hangzhou First People’s Hospital (2025ZN028-1). The animal study protocol was approved by the Institutional Review Board of the Zhejiang Laboratory Animal Center (ZJCLA-IACUC-20011360). Informed Consent Statement Informed consent was obtained from all subjects involved in the study. Competing interests The authors declare no competing interests. Clinical Trial Number Not applicable. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary Information Below is the link to the electronic supplementary material. Rights and permissions Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, 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 changes were made. 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/4.0/. About this article Cite this article Wu, Y., Ye, X., Zheng, A. et al. Targeting E-Selectin and ICAM1 Suppresses Endometriosis Progression by Disrupting the Inflammation–Fibrosis Axis and Reducing Local M2 Macrophage Infiltration. Inflammation (2026). https://doi.org/10.1007/s10753-026-02601-8 Received: Revised: Accepted: Published: DOI: https://doi.org/10.1007/s10753-026-02601-8