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.