Pep-Nur77-R346K peptide rescues endometrial decidualization and boosts fertility by targeting PRMT5-Nur77 axis

Defective endometrial decidualization is a major, yet poorly understood, cause of female infertility and recurrent implantation failure (RIF). Current treatments often fall short due to a lack of precise mechanistic targets. This research addresses the critical gap in understanding the molecular mechanisms governing endometrial receptivity. The study focuses on protein arginine methyltransferase 5 (PRMT5) and the orphan nuclear receptor Nur77, investigating their roles in regulating decidualization capacity and exploring a novel peptide-based therapeutic strategy.

Researchers investigated PRMT5 expression and its role in decidualization using human endometrial stromal cells (EnSCs) and mouse models. They generated uterine stromal-specific Prmt5 ablation mice (Prmt5d/d) and an estrogen-deficient mouse model. Multi-omics analysis in human EnSCs identified PRMT5's interaction with Nur77. A peptide, Pep-Nur77-R346K, was designed to target the PRMT5-Nur77 methylation axis. Its efficacy was tested in PRMT5-deficient human EnSCs, Prmt5d/d mice, pharmacologically inhibited mouse models, estrogen-deficient mice, and primary RIF EnSCs. A retrospective cohort of 114 participants was analyzed to correlate endometrial PRMT5/Nur77-R346me2s levels with pregnancy outcomes.

PRMT5 was found to be upregulated during decidualization and by progesterone stimulation, but markedly downregulated in the endometria of RIF patients, alongside a global reduction of symmetric dimethylarginine (sDMA). Uterine stromal-specific ablation of Prmt5 in mice severely impaired decidualization, leading to infertility. Multi-omics analysis revealed that PRMT5 promotes decidualization by catalyzing sDMA at arginine 346 (R346) of the orphan nuclear receptor Nur77, which is crucial for its proper chromatin occupancy. Targeting this axis, the designed peptide, Pep-Nur77-R346K, successfully rescued decidualization in multiple preclinical models: PRMT5-deficient human EnSCs, both genetic knockout (Prmt5d/d) and pharmacologically inhibited mouse models, an estrogen-deficient mouse model, and, importantly, primary RIF EnSCs.

In a retrospective cohort of 114 participants, correlated reductions of endometrial PRMT5/Nur77-R346me2s were confirmed, demonstrating robust predictive value for pregnancy outcome.