Quercetin enhances decidualization through AKT-ERK-p53 signaling and supports a role for senescence 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 quercetin’s effects are not well-defined. In this report, we have analyzed the signaling pathways underlying quercetin’s 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Northwell Health Innovations Award and the Endometriosis Foundation of America ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of The Feinstein Institutes for Medical Research/Northwell Health gave ethical approval for this work (IRB# #13-376A). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are contained in the manuscript and are available upon reasonable request to the authors