Betulinic Acid Inhibits Endometriosis Through Suppression of Estrogen Receptor β Signaling Pathway.

Endometriosis is an inflammatory gynecological disorder characterized by endometrial tissue growth located outside of the uterine cavity in addition to chronic pelvic pain and infertility. In this study, we aim to develop a potential therapeutic treatment based on the pathogenesis and mechanism of Endometriosis. Our preliminary data showed that the expression of estrogen receptor beta (ER beta) was significantly increased, while ER alpha was significantly decreased, in endometriotic cells compared to normal endometrial cells. Further investigation showed that betulinic acid (BA) treatment suppressed ER beta expression through epigenetic modification on the ER beta promoter, while had no effect on ER alpha expression. In addition, BA treatment suppresses ER beta target genes, including superoxide dismutase 2 (SOD2), nuclear respiratory factor-1 (NRF1), cyclooxygenase 2 (COX2), and matrix metalloproteinase-1 (MMP1), subsequently increasing oxidative stress, triggering mitochondrial dysfunction, decreasing elevated proinflammatory cytokines, and eventually suppressing endometriotic cell proliferation, mimicking the effect of ER beta knockdown. On the other hand, gain of ER beta by lentivirus infection in normal endometrial cells resulted in increased cell proliferation and proinflammatory cytokine release, while BA treatment diminished this effect through ER beta suppression with subsequent oxidative stress and apoptosis. Our results indicate that ER beta may be a major driving force for the development of endometriosis, while BA inhibits Endometriosis through specific suppression of the ER beta signaling pathway. This study provides a novel therapeutic strategy for endometriosis treatment through BA-mediated ER beta suppression.