Zinc Finger Protein 143 Promotes Endometriotic Lesion Growth and Fibrosis through the Plasminogen Activator Inhibitor-1 Pathway.

Endometriosis is a chronic, estrogen-dependent gynecologic disorder characterized by the ectopic growth of endometrial tissue outside the uterus. Zinc finger protein 143 (ZNF143) is a DNA-binding transcription factor, yet its role in endometriosis remains unknown. Here, it is reported that ZNF143 is significantly up-regulated in ectopic endometrial lesions. Invivo, Pgrcre+Zfp143f/f mice were used to achieve conditional deletion of Zfp143 in uterine epithelial and stromal cells via progesterone receptor (Pgr)-driven Cre recombination. Uterine-specific deletion of Zfp143 in this model markedly reduced lesion formation and growth. In contrast, epithelial-specific deletion using Sprr2fcre+Zfp143f/f mice, in which Sprr2f is selectively expressed in uterine epithelial cells, showed no significant effect, indicating that ZNF143 primarily functions in endometrial stromal cells. In vitro, ZNF143 promoted stromal cell migration and invasion while knockdown of ZNF143 using siRNA transfection inhibited migration and invasion of hTERT-immortalized human endometrial stromal cells and primary human endometrial stromal cells. ZNF143 deficiency also reduced collagen deposition in ectopic lesions, implicating it in fibrotic remodeling. Transcriptomic profiling identified plasminogen activator inhibitor-1 (SERPINE1) as a key downstream effector mediating ZNF143-driven fibrosis, and SERPINE1 silencing attenuated these profibrotic effects. Collectively, these findings establish ZNF143 as a critical transcriptional regulator, especially in endometrial stroma that drives lesion progression and fibrosis in endometriosis, providing new mechanistic insights and highlighting a promising therapeutic target.