Abstract
Endometriosis is a common gynecological disease associated with pelvic pain and infertility. Despite several existing theories, the etiology and molecular mechanisms of endometriosis remain to be investigated. Here we report that transcription factor 21 (TCF21) regulates uterine development and endometriosis pathogenesis by promoting epithelial-to-mesenchymal transition (EMT) and cytoskeleton reorganization. Uterine-specific knockout of Tcf21 in mice promotes EMT of the endometrium and dysplasia of the uterus. Accordingly, patients with endometriosis exhibit high TCF21 expression and an expanded population of stromal cells in both eutopic and ectopic endometria. Integrative epigenomic and transcriptomic analyses in patient-derived ectopic stromal cells reveal that TCF21 transcriptionally activated a cohort of genes, including LIMK2, which is critically involved in cytoskeleton organization. Indeed, TCF21-activated LIMK2-cofilin signaling in stromal cells is associated with actin-cytoskeleton reorganization and increased cell invasion and adhesion. In a surgically constructed mouse model, depletion of Tcf21 in eutopic stromal cells alleviates endometriotic lesions, whereas treatment of mice with AAV-Pgr-Tcf21 leads to increased endometriosis incidence, which could be mitigated by administering the LIM kinase inhibitor LIMKi 3. These observations uncover the importance of the TCF21-LIMK2-cofilin axis in uterine development and endometriosis, supporting the pursuit of TCF21-LIMK2-cofilin targeting in the diagnosis and therapeutics of endometriosis.
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Data availability
All data associated with this study are present in the paper. CUT&Tag data for TCF21 and RNA-seq data for paired eutopic and ectopic endometrium have been deposited in the GEO with the accession numbers GSE282592 and GSE282532, respectively. RNA-seq data from the uteri of 6-week-old Tcf21f/f and Tcf21d/d mice have been deposited in the GEO with the accession numbers GSE304889. Source data are provided with this paper.
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Acknowledgements
This work was supported by a grant (2022YFC2704000 to Q.X.) from the Ministry of Science and Technology of China and grants (82273155 to J.L., and 82188102 to Y.S.) from the National Natural Science Foundation of China. We thank all the women who participated in our studies and donated samples.
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Q.X, J.L, and J.W.Z. conceived and designed the project. J.W.Z. performed most of the experiments. P.L.W., D.Y.Z. contributed to patient enrollment and information collection. Y.L.M., H.W.F., Z.J.P., L.Y.Q., M.Y.G., R.H.L., C.Z., N.Wu and C.Y.Z. assisted experimental conduction and data interpretation. C.P., Y.F.Z. performed laparoscopic surgery in patients with endometriosis. J.W.Z., J.L., and Q.X. wrote the manuscript. Y.F.S. reviewed and edited the manuscript.
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Zhu, J., Wu, P., Ma, Y. et al. TCF21 promotes epithelial-to-mesenchymal transition and cytoskeleton reorganization in uterine development and endometriosis. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69551-5
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DOI: https://doi.org/10.1038/s41467-026-69551-5
