Deciphering the Role of ZEB1 as a Central Regulator of Epithelial-Mesenchymal Transition and Hormonal Resistance in Endometriosis

Sanket Shirodkar, Shirodkar S, Gaurav Doshi
Reproductive sciences (Thousand Oaks, Calif.) · 2026 · doi:10.1007/s43032-026-02181-w · PMID:42717122 · W7212073409
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This review identifies ZEB1 as a central regulator of epithelial-mesenchymal transition and progesterone resistance in endometriosis, highlighting its role in lesion persistence and the translational challenges of targeting this axis for precision interventions.

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Abstract

Endometriosis is a chronic inflammatory and sex steroid hormone-dependent gynaecologic disease, characterised by endometrial cell proliferation outside the uterine cavity, often accompanied by fibrosis, progesterone resistance, and high recurrence despite hormonal and surgical interventions. Epithelial-mesenchymal transition (EMT) is important for establishment of lesions and invasiveness, but the upstream transcriptional regulators that integrate hormonal, inflammatory and epigenetic signals are incompletely defined. This review emphasises ZEB1 as a molecular integrator at the systems level in endometriosis pathogenesis. We reviewed evidence for selective upregulation of ZEB1 in ectopic lesions, where it inhibits epithelial adhesion molecules, stabilises mesenchymal differentiation and activates the attachment-invasion angiogenesis cascade required for lesion persistence. In addition to EMT, we discuss bidirectional crosstalk between ZEB1 and endocrine signalling, illustrating how oestrogen-mediated induction and suppression of progesterone receptor pathways converge to establish progesterone resistance. The review includes miR-200 family members, long non-coding RNAs and circular RNAs that strengthen ZEB1 expression through multilayered feedback mechanisms that perpetuate chronic inflammatory and pro-fibrotic microenvironments. Critically, it tackles translational complexity by incorporating the heterogeneity of lesions uncovered through single-cell and spatial transcriptomics, and by assessing the experimental models necessary to determine causal relevance. Additionally, it addresses the paradox of targeting ZEB1 therapeutically, considering its physiological function in endometrial regeneration and implantation. Understanding the oestrogen-ZEB1-TGF-β axis is critical for developing mechanism-based precision interventions for endometriosis.

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chemicals 2
progesterone progesterone

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