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

Dongfang Xiang, Min Zhao, Xiaofan Cai, Yongxia Wang, Lei Zhang, Helen Yao, Min Liu, Huan Yang, Mingtao Xu, Huilin Li, Huijuan Peng, Min Wang, Xuefang Liang, Ling Li, Paul Yao
Frontiers in endocrinology · 2020 · vol. 11 , pp. 604648 · doi:10.3389/fendo.2020.604648 · PMID:33362719 · PMC7759155 · W3112929515
article OA: gold CC0 ⤵ 10 in-corpus citations
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⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

Betulinic acid suppresses estrogen receptor β expression and signaling pathways, thereby inhibiting endometriotic cell proliferation and offering a potential therapeutic strategy for endometriosis.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-10 ⓘ

The study investigated whether betulinic acid (BA) affects estrogen receptor β (ERβ) signaling in endometriotic cells and assessed downstream effects on inflammation, oxidative stress, mitochondrial function, and cell proliferation. Using human endometrial epithelial cells and an immortalized primary endometriotic epithelial line, the authors found ERβ was increased in endometriotic cells, while BA suppressed ERβ (not ERα) by inducing epigenetic changes at the ERβ promoter and reduced ERβ target genes including SOD2, NRF1, COX2, and MMP1, leading to increased oxidative stress, mitochondrial dysfunction, decreased proinflammatory cytokines, and reduced proliferation, paralleling ERβ knockdown. They further showed that lentiviral ERβ overexpression increased proliferation and proinflammatory cytokine release in normal endometrial cells, while BA diminished these effects by suppressing ERβ. This paper is centrally about endometriosis — BA is proposed to inhibit endometriosis by suppressing ERβ signaling and its inflammatory/oxidative downstream pathways.

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Abstract

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 β (ERβ) was significantly increased, while ERα was significantly decreased, in endometriotic cells compared to normal endometrial cells. Further investigation showed that betulinic acid (BA) treatment suppressed ERβ expression through epigenetic modification on the ERβ promoter, while had no effect on ERα expression. In addition, BA treatment suppresses ERβ 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 ERβ knockdown. On the other hand, gain of ERβ by lentivirus infection in normal endometrial cells resulted in increased cell proliferation and proinflammatory cytokine release, while BA treatment diminished this effect through ERβ suppression with subsequent oxidative stress and apoptosis. Our results indicate that ERβ may be a major driving force for the development of endometriosis, while BA inhibits Endometriosis through specific suppression of the ERβ signaling pathway. This study provides a novel therapeutic strategy for endometriosis treatment through BA-mediated ERβ suppression.

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Condition tags

endometriosischronic_pelvic_paininfertility

MeSH descriptors

Anti-Inflammatory Agents, Non-Steroidal Endometriosis Estrogen Receptor beta Gene Expression Regulation Oxidative Stress Pentacyclic Triterpenes Anti-Inflammatory Agents, Non-Steroidal Apoptosis Betulinic Acid Cell Proliferation Cells, Cultured Endometriosis Endometriosis Endometriosis Estrogen Receptor beta Estrogen Receptor beta Estrogen Receptor beta Female Gene Expression Regulation Humans

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