CircFOXO3 mediates hypoxia‐induced autophagy of endometrial stromal cells in endometriosis

• Published in: The FASEB journal 2024-03, Vol.38 (5), p.e23515-n/a
• Main Authors: Zhang, Ling, Liu, Hengwei, Xiong, Wenqian, He, Haitang, Fu, Tian, Long, Xuefeng, Li, Xiaoou, Liang, Jiaxin, Ding, Hui, Xu, Ying, Liu, Yi, Dai, Xin
• Format: Article
• Language: English
• Subjects: ADAR1; autophagy; circFOXO3; circRNA; endometriosis; hypoxia inducible factor 1 alpha (HIF‐1α)
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.202301654RR

Endometriosis is a benign gynecological disease that shares some common features of malignancy. Autophagy plays vital roles in endometriosis and influences endometrial cell metastasis, and hypoxia was identified as the initiator of this pathological process through hypoxia inducible factor 1 alpha (HIF‐1α). A newly discovered circular RNA FOXO3 (circFOXO3) is critical in cell autophagy, migration, and invasion of various diseases and is reported to be related to hypoxia, although its role in endometriosis remains to be elucidated up to now. In this study, a lower circFOXO3 expression in ectopic endometrium was investigated. Furthermore, we verified that circFOXO3 could regulate autophagy by downregulating the level of p53 protein to mediate the migration and invasion of human endometrial stromal cells (T HESCs). Additionally, the effects of HIF‐1α on circFOXO3 and autophagy were examined in T HESCs. Notably, overexpression of HIF‐1α could induce autophagy and inhibit circFOXO3 expression, whereas overexpressing of circFOXO3 under hypoxia significantly inhibited hypoxia‐induced autophagy. Mechanistically, the direct combination between HIF‐1α and HIF‐1α‐binding site on adenosine deaminase 1 acting on RNA (ADAR1) promoter increased the level of ADAR1 protein, which bind directly with circFOXO3 pre‐mRNA to block the cyclization of circFOXO3. All these results support that hypoxia‐mediated ADAR1 elevation inhibited the expression of circFOXO3, and then autophagy was induced upon loss of circFOXO3 via inhibition of p53 degradation, participating in the development of endometriosis. Hypoxia inducible factor 1 alpha (HIF‐1α) and adenosine deaminase 1 acting on RNA (ADAR1) promoter combined increasedly under hypoxia, which promoted the synthesis of ADAR1 protein. ADAR1 protein bound directly with circFOXO3 pre‐mRNA to block the cyclization, and then autophagy was induced upon loss of circFOXO3 via inhibition of p53 degradation. Finally, autophagy promoted ectopic endometrial migration and invasion, participating in the occurrence and development of endometriosis.