Document Type

Article

Publication Date

7-16-2026

Comments

This article is the author’s final published version in The Journal of clinical investigation, Volume 136, Issue 17, 2026, Article number e077471.

The published version is available at https://doi.org/10.1172/JCI178862. Copyright © 2026, Cao et al.

 

Abstract

Defective endometrial decidualization is one major cause of female infertility, yet the underlying mechanisms remain elusive. Here, we identified that protein arginine methyltransferase 5 (PRMT5), which was upregulated during decidualization and by progesterone stimulation, was markedly downregulated in the endometria of patients with recurrent implantation failure (RIF), along with a global reduction of symmetric dimethylarginine (SDMA). Uterine stroma-specific ablation of Prmt5 in mice severely impaired decidualization, leading to infertility. A multiomics analysis in human endometrial stromal cells (EnSCs) revealed that PRMT5 promoted decidualization primarily by catalyzing SDMA at arginine 346 (R346) of the orphan nuclear receptor Nur77, which directs its proper chromatin occupancy. Targeting the PRMT5/Nur77 methylation axis, we designed a peptide, Pep-Nur77R346K, which rescued the decidualization of multiple preclinical models: PRMT5-deficient human EnSCs, both genetic knockout (Prmt5d/d) and pharmacologically inhibited mouse models, and most importantly, primary RIF EnSCs. In a retrospective cohort of 114 participants, the correlated reductions of endometrial PRMT5/Nur77-R346me2s were confirmed, which demonstrated robust predictive value for pregnancy outcome. Our work establishes the PRMT5/Nur77 methylation axis as a key regulator of endometrial receptivity and highlights both a diagnostic biomarker and a peptide-based therapeutic potential for infertility.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

42467593

Language

English

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