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

Zijie An,1,* Yanqing Gong,2,* Xuedan Deng,1,* Yong Xie1,3 1School of Clinical Medicine, Guangdong Medical University, Zhanjiang, Guangdong, People’s Republic of China; 2The Second Clinical Medical School, Southern Medical University, Guangzhou, People’s Republic of China; 3Department of Gynecologic Oncology, Foshan First People’s Hospital, Foshan, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yong Xie, Department of Gynecologic Oncology, Foshan First People’s Hospital, 81, North Lingnan Avenue, Chancheng District, Foshan, Guangdong, 528000, People’s Republic of China, Tel +86-19194302864, Email [email protected]: 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.Aim: To investigate the immunological mechanisms underlying endometriosis and endometrial cancer.Methods: 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.Results: 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 BRI3 expression as being positively associated with endometrial cancer risk, whereas CAPG and ITGAX showed inverse associations. Colocalization confirmed a shared genetic locus for BRI3 between the expression and risk signals. BRI3-positive CD56^dim NK cells were enriched in tumor-associated signaling pathways and pseudotime analysis indicated functional reprogramming during NK cell activation.Conclusion: This study supports a causal link between endometriosis and endometrial cancer mediated by NK cell–specific genetic mechanisms, with BRI3 representing a potential biomarker and therapeutic target. Further functional studies and longitudinal cohort studies are required to validate these findings.Keywords: endometriosis, endometrial cancer, natural killer cells, single-cell RNA sequencing, Mendelian randomization