How Epithelial-to-Mesenchymal Transition Alters Estradiol Metabolism in Endometriotic Cells?

Targeting the TGF-β-Snail Pathway may Restore Estradiol Metabolism to Offer A New Therapeutic Direction.

Key Points

Highlight:

• TGF-β–induced EMT suppresses HSD17B2 through Snail-mediated transcriptional repression, linking inflammation-driven epithelial to mesenchymal transition (EMT) to local estrogen excess in endometriosis.

Importance:

• Findings help explain why endometriosis lesions maintain elevated local estradiol levels despite systemic hormonal regulation, highlighting potential therapeutic targets within the TGF-β/Snail signaling pathway.

What's Done Here?

• Researchers used human endometrial and endometriotic epithelial cell models to examine how TGF-β–induced EMT affects HSD17B2 expression.
• EMT induction and changes in HSD17B2 were assessed using qPCR, Western blotting, and immunohistochemistry.
• Snail’s regulatory role was evaluated through overexpression and knockdown experiments, along with luciferase promoter assays to confirm direct transcriptional repression of HSD17B2.

Key Results:

• TGF-β treatment induced EMT features and significantly downregulated HSD17B2 expression in endometriotic epithelial cells.
• Snail overexpression recapitulated this suppression, while Snail knockdown restored HSD17B2 levels.
• Promoter assays confirmed direct transcriptional repression of HSD17B2 by Snail.
• Loss of HSD17B2 impairs the conversion of estradiol (E2) to estrone (E1), supporting a model of EMT-driven estrogen imbalance in endometriosis.

Strengths and Limitations:

• Strengths are, mechanistic experiments demonstrating causal links between EMT activation, Snail signaling, and estradiol-metabolizing enzymes; multiple complementary techniques confirming transcriptional regulation.
• Limitations are: in vitro design limits physiological generalizability; absence of in vivo functional validation; and potential involvement of additional EMT regulators not evaluated in this study.

From the Editor-in-Chief – EndoNews

"One of the most persistent questions in endometriosis research is why lesions are able to sustain a highly estrogenic microenvironment, even when systemic hormone levels do not fully support such activity. This study provides an important mechanistic insight by linking a well-described inflammatory signaling pathway—TGF-β–driven epithelial–mesenchymal transition (EMT)—to the transcriptional repression of HSD17B2, a pivotal enzyme responsible for inactivating estradiol.

The authors demonstrate that EMT is not merely a phenotypic transformation associated with increased cellular motility, but also a molecular program with direct metabolic consequences. The identification of Snail as a transcriptional repressor of HSD17B2 is particularly notable. Snail has long been recognized as a central EMT driver, but its involvement in steroid metabolism has not been as clearly defined. By establishing that Snail binds to and suppresses the HSD17B2 promoter, the authors provide a mechanistic bridge between inflammation-induced cellular reprogramming and dysregulated estrogen metabolism—a connection that has been hypothesized but not previously demonstrated with this level of molecular detail.

These findings advance the conceptual framework through which we understand endometriosis. They highlight a reciprocal interaction: inflammatory cytokines such as TGF-β promote EMT, EMT activates transcription factors like Snail, and Snail in turn alters the hormonal milieu in a way that favors lesion survival and persistent inflammation. This feed-forward loop helps explain why endometriosis remains active even in hormonal environments that would typically suppress endometrial proliferation.

Methodologically, the study is strengthened by its use of complementary approaches—including EMT induction, Snail overexpression and knockdown, and promoter-level assays—to support a causal chain of events rather than simple correlation. Still, the work is limited by its reliance on in vitro models, and in vivo validation will be essential to confirm the broader physiologic relevance. Additional EMT-associated regulators may also modulate HSD17B2, and future studies should explore these pathways in the context of disease heterogeneity.

Clinically, the implications are intriguing. If EMT programs directly sustain high intra-lesional estradiol levels, therapeutic strategies targeting upstream regulators such as TGF-β signaling, EMT transcription factors, or even the restoration of HSD17B2 activity could complement traditional hormonal therapies. This could be particularly relevant for patients who do not respond fully to systemic hormone suppression.

Overall, this study deepens our understanding of the molecular circuitry operating within endometriotic lesions and provides a compelling mechanistic link between inflammation, cellular reprogramming, and estrogen metabolism. It contributes meaningfully to the ongoing shift toward viewing endometriosis as a biologically dynamic and metabolically adaptable disease, rather than a purely hormone-dependent condition."

Lay Summary

Researchers are increasingly uncovering how endometriosis behaves not just as a hormonal disorder but as a condition shaped by complex cellular signaling pathways. A new study published in Biochemical and Biophysical Research Communications helps explain why endometriotic lesions are able to maintain high levels of estrogen, which fuels their growth and survival.

The study focuses on a cellular process called epithelial–mesenchymal transition (EMT). In EMT, cells that normally behave like tightly connected “epithelial” cells begin to act more like flexible, mobile “mesenchymal” cells. EMT is known to occur in endometriosis, making lesions more invasive and harder to treat.

One of the strongest triggers of EMT is TGF-β, a signaling molecule frequently elevated in endometriotic tissue. When TGF-β is present, endometrial cells begin to change their behavior and activate genes associated with inflammation, migration, and survival.

The researchers examined how this TGF-β–induced EMT affects a specific enzyme, HSD17B2, which normally converts active estradiol (E2) into a weaker estrogen (E1). When HSD17B2 levels fall, estradiol accumulates inside lesions, worsening inflammation and pain.

A key discovery of the study is the role of Snail, a transcription factor activated during EMT. Snail can turn genes “off” by binding to their promoter regions. The authors showed that Snail directly suppresses the HSD17B2 gene, preventing the breakdown of estradiol. As a result, EMT does not only change how cells look and behave—it also creates a hormonal environment that favors lesion growth.

To test these mechanisms, the researchers treated endometrial and endometriotic epithelial cells with TGF-β, induced EMT, and measured changes in gene and protein expression. They then manipulated Snail levels and used promoter-binding assays to confirm that Snail directly shuts down HSD17B2.

Taken together, the findings provide a molecular explanation for why endometriotic lesions maintain high estrogen levels even when the rest of the body does not. By linking TGF-β signaling, EMT activation, and Snail-mediated gene repression, the study identifies a pathway that could become a future therapeutic target.

These results highlight how endometriosis is sustained not only by hormones but also by cellular reprogramming and inflammatory signaling, opening the door to new strategies that go beyond traditional hormonal therapies.

Research Source: https://pubmed.ncbi.nlm.nih.gov/40393157/