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ResearchIn-Press PreviewGeneticsReproductive biology Open Access | 10.1172/JCI178862

Targeting the PRMT5-Nur77 methylation axis enhances endometrial decidualization capacity and female fertility in preclinical models

Zhiwen Cao,1 Xinyu Cai,1 Jie Mei,1 Na Kong,1 Yang Liu,1 Xiaoyue Shen,1 Min Wu,1 Xin Zhen,1 Jianxin Sun,2 Rong Li,1 Ruiwei Jiang,1 Haixiang Sun,1 and Guijun Yan1

1Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing University, Nanjing, China

2Department of Medicine, Thomas Jefferson University, Philadelphia, United States of America

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1Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing University, Nanjing, China

2Department of Medicine, Thomas Jefferson University, Philadelphia, United States of America

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1Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing University, Nanjing, China

2Department of Medicine, Thomas Jefferson University, Philadelphia, United States of America

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1Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing University, Nanjing, China

2Department of Medicine, Thomas Jefferson University, Philadelphia, United States of America

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1Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing University, Nanjing, China

2Department of Medicine, Thomas Jefferson University, Philadelphia, United States of America

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1Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing University, Nanjing, China

2Department of Medicine, Thomas Jefferson University, Philadelphia, United States of America

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1Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing University, Nanjing, China

2Department of Medicine, Thomas Jefferson University, Philadelphia, United States of America

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1Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing University, Nanjing, China

2Department of Medicine, Thomas Jefferson University, Philadelphia, United States of America

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1Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing University, Nanjing, China

2Department of Medicine, Thomas Jefferson University, Philadelphia, United States of America

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1Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing University, Nanjing, China

2Department of Medicine, Thomas Jefferson University, Philadelphia, United States of America

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1Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing University, Nanjing, China

2Department of Medicine, Thomas Jefferson University, Philadelphia, United States of America

Find articles by Jiang, R. in: PubMed | Google Scholar

1Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing University, Nanjing, China

2Department of Medicine, Thomas Jefferson University, Philadelphia, United States of America

Find articles by Sun, H. in: PubMed | Google Scholar

1Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing University, Nanjing, China

2Department of Medicine, Thomas Jefferson University, Philadelphia, United States of America

Find articles by Yan, G. in: PubMed | Google Scholar

Published July 17, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI178862.
Copyright © 2026, Cao et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 17, 2026 - Version history
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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, is markedly down-regulated in the endometria of patients with recurrent implantation failure (RIF), along with a global reduction of symmetric dimethylarginine (sDMA). Uterine stromal-specific ablation of Prmt5 in mouse severely impaired decidualization leading to infertility. A multi‑omics 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‑Nur77-R346K, which rescued the decidualization of multiple preclinical models: PRMT5 deficient human EnSCs, both genetic knockout (Prmt5d/d) and pharmacologically inhibited mouse models, an estrogen deficient mouse model, and, more importantly, the primary RIF EnSCs. In a retrospective cohort of 114 participants, the correlated reductions of endometrial PRMT5/Nur77-R346me2s was 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 novel diagnostic biomarker and a peptide‑based therapeutic potential for fertility.

Graphical Abstract
graphical abstract
Supplemental material

View Table S1 patient information

View Table S2 LH hendo DEGs

View Table S3 SDMA DEPs

View Table S4 RIF pathway

View Table S5 shPRMT5 DEGs pathway

View Table S6 PRMT5 IP

View Table S7 PRMT5-Nur77 DEG pathway

View Table S8 Nur77 peak DEGs

View Table S9 Correlation analysis clinical

View Table S10 Antibodies and primers

View Unedited blot and gel images

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Version history
  • Version 1 (July 17, 2026): In-Press Preview
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