Immune-associated molecular alterations in intrauterine adhesion highlight potential targets for fibrotic endometrial remodeling

Intrauterine adhesion (IUA) is characterized by progressive endometrial fibrosis and impaired regeneration, leading to menstrual abnormalities and infertility. Increasing evidence suggests that dysregulated immune responses contribute to adhesion formation; however, the molecular regulators linking inflammation to fibrotic remodeling remain unclear. We investigated molecular alterations associated with IUA using transcriptomic analysis of a rat endometrial injury model, followed by assessment in an independent human dataset from the Gene Expression Omnibus (GEO). Differential expression analysis, network-based analysis, and immune-cell deconvolution were performed to identify key pathways and candidate regulators. Selected genes were validated by RT-qPCR, western blotting, and immunohistochemistry. Drug–gene interaction analysis and molecular docking were used to screen candidate compounds and examine their predicted interactions with the selected proteins. Transcriptomic profiling revealed significant enrichment of pathways associated with inflammation, oxidative stress, and extracellular matrix remodeling in IUA tissues. The estimated proportions of follicular helper T cells, resting dendritic cells, and neutrophils were higher in IUA tissues, whereas those of resting CD4⁺ memory T cells and resting NK cells were lower. Integrated analysis and experimental validation identified CYBB (NOX2), EXO1, and IGF1 as key genes associated with IUA. CYBB and EXO1 were upregulated, whereas IGF1 was downregulated. The expression levels of these genes were correlated with the estimated proportions of several immune-cell subsets. Molecular docking suggested potential binding of apigenin and chrysin to CYBB, capecitabine to EXO1, and trofinetide to IGF1. Persistent immune activation, together with impaired regenerative signaling, may contribute to fibrotic remodeling of the endometrium in IUA. CYBB, EXO1, and IGF1 may represent candidate biomarkers associated with IUA and warrant further functional validation.