Bidirectional Mendelian Randomization and Single‑Cell RNA Sequencing Reveal an NK Cell-Mediated Causal Link Between Endometriosis and Endometrial Cancer

<h4>Background</h4>Endometriosis is a chronic estrogen-dependent inflammatory disease that shares epidemiological and pathological features with endometrial cancer. However, the cellular and genetic mechanisms underlying this association remain unclear.<h4>Aim</h4>To investigate the immunological mechanisms underlying endometriosis and endometrial cancer.<h4>Methods</h4>Single-cell RNA sequencing was performed on endometrial tissues from patients with endometriosis and endometrial cancer to profile Natural Killer (NK) cell subsets and intercellular communication. Differential gene expression in CD56dim NK cells was integrated into a genome-wide association study and expression quantitative trait loci datasets for bidirectional Mendelian randomization and genetic colocalization analyses.<h4>Results</h4>CD56dim NK cells constituted the dominant NK cell subset in both diseases, showing divergent communication networks between epithelial and endothelial cells in cancer. Mendelian Randomization (MR) analysis identified genetically predicted <i>BRI3</i> expression as being positively associated with endometrial cancer risk, whereas <i>CAPG</i> and <i>ITGAX</i> showed inverse associations. Colocalization confirmed a shared genetic locus for <i>BRI3</i> between the expression and risk signals. <i>BRI3</i>-positive CD56^dim NK cells were enriched in tumor-associated signaling pathways and pseudotime analysis indicated functional reprogramming during NK cell activation.<h4>Conclusion</h4>This study supports a causal link between endometriosis and endometrial cancer mediated by NK cell-specific genetic mechanisms, with <i>BRI3</i> representing a potential biomarker and therapeutic target. Further functional studies and longitudinal cohort studies are required to validate these findings.