Single-Cell RNA Sequencing Reveals Immune Dysregulation and Candidate Drug Targets in Endometriosis

Endometriosis is a chronic inflammatory disorder affecting 5–10% of women of reproductive age and is associated with chronic pain and infertility. While research has mainly focused on local lesions, systemic immune dysfunction is increasingly implicated in disease pathogenesis. This study employs single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from women with endometriosis and unaffected controls, combined with integrative analysis of publicly available datasets of menstrual blood and endometrial tissues, to uncover immune dysregulation and therapeutic targets in endometriosis. Cell-type composition and pathway alterations were assessed. Upregulated genes were evaluated using pharmacophore modeling, virtual screening, molecular docking of approved drugs, and molecular dynamics simulations to explore therapeutic potential. Immune profiling revealed increased B- and T-cell subsets and widespread inflammatory dysregulation. Notably, HSP90AA1 and PLCG2 (linked to endometrial cell survival and angiogenesis) were consistently upregulated across datasets, emerging as biologically plausible candidate drug targets for therapeutic intervention. Computational drug repurposing analysis prioritized upadacitinib, sorafenib, alpelisib, and sulindac as hypothetical candidates for further investigation, with molecular docking identifying favorable predicted binding affinity scores, particularly for HSP90AA1. These results reinforce a systemic, immune-mediated view of endometriosis and nominate HSP90AA1 and PLCG2 as novel candidate targets that now require biochemical, chemical, and in vivo validation.