Immunological Dysregulation in Endometriosis Potentially Linked to Anomalies in NCOA4-Mediated Iron Autophagy Pathway

Abstract

Abstract Objective This study aims to investigate the expression disparities of Nuclear Receptor Coactivator 4 (NCOA4) in endometriosis (EMS) patients, assessing its diagnostic potential. It also elucidate the correlation between the immune microenvironment in EMS patients and pivotal genes in iron autophagy,and seeks to corroborate the activation status of the NCOA4-mediated iron autophagy pathway in both ectopic and eutopic endometrial tissues in EMS, Methods "Data sets from microarrays pertaining to EMS patients were obtained from the GEO database. This was done to analyze the differential expression of NCOA4 in both ectopic and eutopic endometrial tissues, in comparison to normal endometrial tissues. The diagnostic efficacy of key iron autophagy genes in identifying EMS was projected using Area Under the Receiver Operating Characteristic Curve (AUROC). This study also further examined the differential immune landscape between ectopic and eutopic endometrial tissues of EMS patients and controls. Additionally, it analyzed the interplay between immune cells, immune checkpoint genes, and key iron autophagy genes in EMS patients. A rat model of EMS was employed to validate the expression patterns of the NCOA4-mediated iron autophagy pathway in ectopic and eutopic endometrium. Results NCOA4 was differentially expressed in endothelial tissues of EMS patients, including two diametrically opposed trends of up-regulation and down-regulation in the in situ endothelial tissues of EMS patients and up-regulation in the ectopic endothelial tissues; Immune infiltration analysis showed that a variety of immune cells and immune checkpoint genes were abnormal in the endothelial tissues of EMS patients, and most of the abnormal immune cells and immune checkpoint genes were strongly correlated with the key genes of iron autophagy, NCOA4, FTH1, LC3B, and P62; Animal results showed that iron autophagy signaling pathway activation was progressively enhanced from the in situ endometrium to the normal endometrium to the ectopic endometrium. Conclusion Restoring the normal function of the NCOA4-mediated iron autophagy signaling pathway by regulating it can block the development of EMS, and its mechanism may be related to improving the local microenvironmental immune imbalance in EMS endothelial tissues.