Single-Cell Transcriptomics Reveals Rora-Associated Aberrant Granulosa Cell Differentiation in Polycystic Ovary Syndrome.
4 affiliations
- 1Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China.
- 2Department of Breast and Thyroid Surgery, Tianjin Union Medical Center, Nankai University, Tianjin, 300121, People's Republic of China.
- 3Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China.
- 4School of Clinical Medicine, Tsinghua University, Beijing, 100084, People's Republic of China.
Abstract
Introduction
Polycystic ovary syndrome (PCOS) is characterized by follicular developmental arrest, yet the molecular basis underlying impaired granulosa cell (GC) differentiation remains incompletely understood.Methods
We constructed a single-cell transcriptomic atlas of ovaries from DHEA-induced PCOS-like mice and matched vehicle controls, and leveraged spatial transcriptomics as an orthogonal reference for major cell-type annotation, followed by in-depth profiling of GC heterogeneity. Pseudotime inference, co-expression networks, and regulon activity analysis were integrated, and findings were validated in independent human GC datasets. In silico Rora perturbation, cell-cell communication analysis, and drug repositioning were additionally performed.Results
We identified a subset of luteinized mural GCs with robust Rora regulon activation, termed Rora-regulon-active GCs. This subset was markedly enriched in PCOS and was reproducibly observed in independent human GC datasets. Rora-regulon-active GCs exhibited an incomplete luteinization phenotype coupled with lipid-metabolic reprogramming. In silico Rora knockdown partially reconfigured GC differentiation trajectories and shifted the PCOS-skewed subset composition toward control, with concordant changes in metabolic transcriptional programs. Cell-cell communication analyses implicated stromal-derived Mdk-Sdc1 signaling and suggested additional crosstalk with macrophages potentially mediated by ligands such as Vegfa. In silico drug repositioning prioritized betaine hydrochloride and bempedoic acid as candidate therapeutics.Discussion
Our study delineates a Rora-associated aberrant GC differentiation program linked to PCOS, nominating this aberrant program as a potential cellular basis of PCOS-associated follicular arrest and providing mechanistic and translational leads for precision-targeted therapy.
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BibTeX
@article{ji2026singlecell,
title = {{Single-Cell Transcriptomics Reveals Rora-Associated Aberrant Granulosa Cell Differentiation in Polycystic Ovary Syndrome.}},
author = {Pengcheng Ji and Shihao Sun and Xiaoyan Xu and Shuang Chen},
journal = {International journal of women's health},
year = {2026},
month = oct,
doi = {10.2147/ijwh.s638672},
url = {https://europepmc.org/article/MED/42927345},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Single-Cell Transcriptomics Reveals Rora-Associated Aberrant Granulosa Cell Differentiation in Polycystic Ovary Syndrome.
AU - Pengcheng Ji
AU - Shihao Sun
AU - Xiaoyan Xu
AU - Shuang Chen
PY - 2026
DA - 2026/10/20
JO - International journal of women's health
DO - 10.2147/ijwh.s638672
UR - https://europepmc.org/article/MED/42927345
AB - Introduction Polycystic ovary syndrome (PCOS) is characterized by follicular developmental arrest, yet the molecular basis underlying impaired granulosa cell (GC) differentiation remains incompletely understood.Methods We constructed a single-cell transcriptomic atlas of ovaries from DHEA-induced PCOS-like mice and matched vehicle controls, and leveraged spatial transcriptomics as an orthogonal reference for major cell-type annotation, followed by in-depth profiling of GC heterogeneity. Pseudotime inference, co-expression networks, and regulon activity analysis were integrated, and findings were validated in independent human GC datasets. In silico Rora perturbation, cell-cell communication analysis, and drug repositioning were additionally performed.Results We identified a subset of luteinized mural GCs with robust Rora regulon activation, termed Rora-regulon-active GCs. This subset was markedly enriched in PCOS and was reproducibly observed in independent human GC datasets. Rora-regulon-active GCs exhibited an incomplete luteinization phenotype coupled with lipid-metabolic reprogramming. In silico Rora knockdown partially reconfigured GC differentiation trajectories and shifted the PCOS-skewed subset composition toward control, with concordant changes in metabolic transcriptional programs. Cell-cell communication analyses implicated stromal-derived Mdk-Sdc1 signaling and suggested additional crosstalk with macrophages potentially mediated by ligands such as Vegfa. In silico drug repositioning prioritized betaine hydrochloride and bempedoic acid as candidate therapeutics.Discussion Our study delineates a Rora-associated aberrant GC differentiation program linked to PCOS, nominating this aberrant program as a potential cellular basis of PCOS-associated follicular arrest and providing mechanistic and translational leads for precision-targeted therapy.
SN - 1179-1411
ER -