The study by Hewitt et al. reported that Zinc Finger MIZ-Type Containing 1 (ZMIZ1) cooperates with estrogen receptor-α (ESR1) to regulate estrogen-responsive transcription essential for uterine proliferation and differentiation (1). In healthy endometrium (left column): Upon estrogen stimulation, ESR1 recruits ZMIZ1 to estrogen-responsive super enhancers. The ESR1-ZMIZ1 complex amplifies transcription of key downstream genes — including Foxm1, Ccna2, and Pgr — that govern epithelial cell-cycle progression, induction of stromal progesterone receptor, and progesterone-dependent decidualization. Coordinated activation of these pathways sustains epithelial proliferation, stromal remodeling, endometrial receptivity, and fertility, preserving uterine homeostasis. In the setting of ZMIZ1 deficiency (right column): Loss or reduction of ZMIZ1 disrupts ESR1-mediated transcriptional programs, resulting in decreased Foxm1, Ccna2, and Pgr expression, defective epithelial proliferation, and impaired stromal differentiation. Dysregulated estrogen signaling enhances SMAD/TGF-β pathway activity, leading to excessive extracellular matrix deposition, collagen accumulation, and progressive age-dependent uterine fibrosis. These molecular defects culminate in infertility, attenuated decidual response, and fibrotic remodeling observed in Zmiz1d/d mice. ZMIZ1 mutations have been detected in endometrial carcinoma, and diminished ZMIZ1 expression in the eutopic endometrium of women with endometriosis is associated with infertility, endometriosis, and endometrial cancer, underscoring the translational relevance of ZMIZ1 dysregulation.