Quercetin, a senolytic, enhances endometrial stromal cell decidualization through AKT and p53 signaling and reveals the potential role of senescent stromal cells in endometriosis

Quercetin, a flavonoid with senolytic activity, has attracted great interest as a therapy for fibrotic diseases such as pulmonary fibrosis, a disorder attributed to senescent pulmonary fibroblasts. Interestingly, quercetin has shown some benefit in pre-clinical models of endometriosis, an inflammatory condition characterized by senescent endometrial stromal cells and in severe cases, intraperitoneal fibrotic lesions and infertility. Quercetin exerts multiple biological activities but the signaling pathways underlying quercetins effects are not well-defined. In this report, we have analyzed the signaling pathways underlying quercetins action using menstrual effluent-derived endometrial stromal cells. We found that quercetin promotes decidualization, a well-defined differentiation process known to be defective in patients with endometriosis using cells obtained from endometriosis patients and unaffected controls. We show that quercetin substantially reduces the phosphorylation of multiple signaling molecules in the AKT and ERK1/2 pathways. In contrast, we observed striking phosphorylation of p53 and increased p53 protein expression. Furthermore, p53 inhibition blocks decidualization while p53 activation promotes decidualization. Finally, we provide evidence that quercetin increases apoptosis of endometrial stromal cells with a senescence phenotype. These data provide insight into mechanisms of action of quercetin in the setting of endometriosis and support studies to test senolytics for treating endometriosis.