Endometriosis, a chronic inflammatory condition affecting an estimated one in ten women of reproductive age, has long frustrated clinicians with its stubborn tendency to recur despite surgery and hormone therapy. A new review published in Reproductive Sciences argues that the answer to this therapeutic failure may lie in a single transcription factor: ZEB1, or Zinc Finger E-Box Binding Homeobox 1. Written by Gaurav Doshi and Sanket Shirodkar of SVKM’s Dr. Bhanuben Nanavati College of Pharmacy in Mumbai, the review synthesises evidence from across the field to position ZEB1 as a master molecular integrator—converging hormonal, inflammatory and epigenetic signals into a single programme that drives lesion establishment, invasiveness and drug resistance.
The biological centrepiece of the review is epithelial–mesenchymal transition, or EMT, the process by which epithelial cells lose their adhesive, stationary character and acquire the migratory, invasive traits of mesenchymal cells. In endometriosis, EMT is thought to be essential for the survival of endometrial cells that reflux into the pelvic cavity during menstruation and subsequently implant on peritoneal surfaces, ovaries and other ectopic sites. ZEB1 sits at the apex of this programme. It suppresses CDH1, the gene encoding E-cadherin, the principal adhesion molecule holding epithelial sheets together, and in doing so dismantles the cell–cell junctions that would otherwise keep ectopic cells anchored and vulnerable. The review details how ZEB1 accomplishes this repression by recruiting chromatin-remodelling machinery, notably the SWI/SNF ATPase subunit BRG1, to the E-cadherin promoter, effectively silencing it epigenetically. The result is a stabilised mesenchymal differentiation that permits attachment, invasion and, ultimately, the vascularisation required for a lesion to persist.
Crucially, the authors argue that ZEB1 is not merely one EMT factor among many, such as SNAI1, SNAI2 or its paralog ZEB2, but a systems-level hub. Immunohistochemical and molecular studies have repeatedly shown selective upregulation of ZEB1 in ectopic endometriotic lesions compared with matched eutopic endometrium, and its expression is particularly pronounced in deep infiltrating disease. One frequently cited clinical study found ZEB1 expression to be a potential indicator of invasive endometriosis, while a pilot investigation of different disease phenotypes has extended these observations across superficial, ovarian and deep infiltrating subtypes. Measurable ZEB levels have even been detected in plasma and peritoneal fluid of patients with endometriosis and infertility, raising the prospect of ZEB-family proteins as circulating biomarkers.
Perhaps the most consequential section of the review concerns the bidirectional crosstalk between ZEB1 and sex steroid signalling. Endometriosis is a hormone-dependent disease, and its defining therapeutic problem is progesterone resistance: lesions fail to respond to the progestational drugs used to suppress them. The review marshals evidence that oestrogen, specifically 17β-estradiol, induces ZEB1 expression, and that ZEB1 in turn suppresses progesterone receptor pathways. This creates a self-reinforcing circuit in which the oestrogen-ZEB1 axis dismantles the molecular machinery that progesterone therapy depends upon. Experimental work has demonstrated that high ZEB1 expression accompanies 17β-estradiol-induced EMT in endometriotic cells, and parallel findings from other hormone-driven diseases reinforce the mechanism: in breast cancer, ZEB1 induces oestrogen receptor-α promoter hypermethylation and confers antiestrogen resistance, and ZEB-family members have been shown to regulate endocrine therapy sensitivity through both canonical and non-canonical routes. In endometriosis, EMT itself has been shown to contribute to the downregulation of progesterone receptor expression in lesions, and the near-uniform loss of progesterone receptor isoform B in ectopic tissue is a long-standing observation that the ZEB1 framework now helps to explain mechanistically.
The review also devotes substantial attention to the non-coding RNA dimension of ZEB1 regulation, describing a multilayered feedback architecture that locks the mesenchymal state in place. The miR-200 family of microRNAs normally targets the 3′ untranslated regions of ZEB1 and ZEB2 transcripts, holding EMT in check. In ectopic lesions, this double-negative feedback loop is subverted: ZEB1 represses miR-200 transcription, and the resulting loss of miR-200 pressure allows ZEB1 protein to accumulate. Long non-coding RNAs add another tier. The lncRNA AFAP1-AS1, for example, promotes EMT in endometriosis in a ZEB1-correlated manner, and the metastasis-associated transcript MALAT1 has been implicated in the same circuitry, with miR-200c suppressing endometriotic progression in vitro and in vivo by targeting it. Circular RNAs complete the picture. The circRNA circZFPM2 has been shown to promote EMT by sponging miR-205-5p and thereby releasing ZEB1 from repression, while hsa_circ_0063526 acts through the miR-141-5p/EMT axis and circATRNL1 acts upstream by upregulating the EMT cofactor YAP1. Together these competing endogenous RNA networks—a concept also validated in metastatic cancer by J Clin Invest work—build a ceRNA web that perpetuates ZEB1 expression long after the initial pro-EMT stimulus has passed.
The authors then connect ZEB1 to the two great downstream consequences of endometriotic lesions: chronic inflammation and fibrosis. Through interactions with the TGF-β pathway—upstream signals such as TGF-β1 activate SMAD2/3, which cooperate with ZEB1 to drive the mesenchymal programme—ZEB1-linked cells reshape the lesion microenvironment. Fibroblast-to-myofibroblast transdifferentiation, marked by α-smooth muscle actin expression, generates the dense extracellular matrix characteristic of endometriotic implants, and analogous MRTF-A–ZEB1–IRF9 axes have been documented in renal fibrosis. Inflammation completes the loop: pro-inflammatory cytokines such as TNF-α, IL-6 and IL-10, and peritoneal fluid cytokine profiles that differ across endometriosis subphenotypes, feed back into EMT signalling through MAPK, ERK, PI3K/AKT and NF-κB pathways, while immune evasion mechanisms—including indoleamine 2,3-dioxygenase-mediated suppression of natural killer cell cytotoxicity—shield ectopic tissue from immune clearance. ZEB1’s own roles in immune cell biology and in macrophage efferocytosis and mitochondrial dynamics add further dimensions to this immunological interplay.
A distinctive strength of the review is its engagement with modern genomics and the heterogeneity it has revealed. Single-cell transcriptomic analyses of endometriosis, published in Nature Genetics and the Journal of Pathology, have identified distinct hormonal, immunologic and inflammatory signatures among the cell populations constituting lesions, and spatial transcriptomics is beginning to map how intermediate fibroblast and myeloid cell distributions shape lesion architecture. ZEB1 expression, the authors note, is not uniform: it varies by lesion subtype, anatomical site and microenvironmental context, which helps explain why superficial peritoneal, ovarian endometrioma and deep infiltrating disease behave so differently and respond so unevenly to therapy. This heterogeneity argues strongly against a one-size-fits-all anti-ZEB1 strategy and supports the emerging precision-medicine framing of the oestrogen-ZEB1-TGF-β axis as the central therapeutic target.
The review is refreshingly candid about the translational paradox at the heart of any ZEB1-directed therapy. Far from being a purely pathological molecule, ZEB1 has indispensable physiological functions in the female reproductive tract. In vitro studies show that ZEB1 modulates endometrial receptivity through EMT in endometrial epithelial cells, and work in mice demonstrates that it promotes EMT of endometrial epithelium and plays a critical role in embryo implantation. ZEB1 is also detected in granulosa cells of women undergoing IVF, regulates wound angiogenesis and closure, participates in corneal homeostasis, and contributes to endometrial repair during menstruation through epithelial migration and mesenchymal–epithelial transition. Blanking ZEB1 systemically, therefore, risks impairing fertility, tissue regeneration and wound healing—the very outcomes clinicians are trying to protect. Any therapeutic strategy would need to be lesion-specific, temporally controlled and carefully titrated, perhaps by targeting upstream oestrogen-driven induction, the TGF-β/ALK5 arm, the non-coding RNA sponges, or post-translational stabilisation mechanisms such as ZEB1 acetylation, phosphorylation and ubiquitin-proteasome turnover via regulators like USP51 and SIAH1/2.
The authors also stress the need for better experimental models to establish causal rather than merely correlative relevance. shRNA- and siRNA-based knockdown of ZEB1 in endometriotic cells, three-dimensional patient-derived endometriosis models for drug evaluation, and multi-omics approaches that integrate transcriptomic, epigenomic and proteomic data—including recent ubiquitination-focused studies of endometriosis fibrosis—are all highlighted as tools that could convert the ZEB1 hypothesis into testable interventions. Biomarker development is another avenue: ZEB-family levels in plasma and peritoneal fluid, in combination with existing miRNA signatures, could one day support non-invasive diagnosis, a long-standing unmet need given that current detection still relies on laparoscopy.
Ultimately, the review’s central claim is that the oestrogen–ZEB1–TGF-β axis functions as a signalling hub through which the hormonal, inflammatory and epigenetic drivers of endometriosis converge and perpetuate one another. By identifying ZEB1 as the point of integration, the authors provide a mechanistic scaffold that could explain progesterone resistance, fibrotic progression and recurrence within a single framework, and they chart a cautious but concrete path toward mechanism-based, lesion-specific precision therapies. For a disease that has historically been managed with blunt hormonal and surgical instruments, the prospect of intervening at the level of a single, druggable transcriptional circuit represents one of the more compelling conceptual advances in endometriosis research in recent years.
Subject of Research: The role of the transcription factor ZEB1 as a central regulator of epithelial–mesenchymal transition and hormonal resistance in endometriosis
Subject of Research: Medicine
Article Title: Deciphering the Role of ZEB1 as a Central Regulator of Epithelial–Mesenchymal Transition and Hormonal Resistance in Endometriosis
Article References: Doshi, G., & Shirodkar, S. (2026). Deciphering the Role of ZEB1 as a Central Regulator of Epithelial–Mesenchymal Transition and Hormonal Resistance in Endometriosis. Reproductive Sciences. https://doi.org/10.1007/s43032-026-02181-w
Image Credits: AI Generated
DOI: 10.1007/s43032-026-02181-w
Keywords: Endometriosis, ZEB1, Epithelial-mesenchymal transition (EMT), Progesterone resistance, Oestrogen signalling, TGF-β signalling, Non-coding RNAs, Fibrosis, miR-200 family, Single-cell transcriptomics
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Ophelia Keating. (September 10, 2026). ZEB1 Drives Epithelial-Mesenchymal Transition and Hormone Resistance in Endometriosis. Scienmag. https://scienmag.com/zeb1-drives-epithelial-mesenchymal-transition-and-hormone-resistance-in-endometriosis/
Ophelia Keating. “ZEB1 Drives Epithelial-Mesenchymal Transition and Hormone Resistance in Endometriosis.” Scienmag, 10 September 2026, https://scienmag.com/zeb1-drives-epithelial-mesenchymal-transition-and-hormone-resistance-in-endometriosis/. Accessed 10 September 2026.
Ophelia Keating. “ZEB1 Drives Epithelial-Mesenchymal Transition and Hormone Resistance in Endometriosis.” Scienmag. September 10, 2026. https://scienmag.com/zeb1-drives-epithelial-mesenchymal-transition-and-hormone-resistance-in-endometriosis/
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