Work

Single-Cell Transcriptomics Reveals Rora-Associated Aberrant Granulosa Cell Differentiation in Polycystic Ovary Syndrome

Year: 2026

Type: article

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.

Source: International Journal of Women s Health

DOI: 10.2147/ijwh.s638672

Authors: Pengcheng Ji, Shihao Sun, Xiaoyan Xu, Shuang Chen

Institutions: First Affiliated Hospital of Zhengzhou University, Nankai University, Zhengzhou University, Tsinghua University

Language: English

Topic: Ovarian function and disorders

Subfield: Reproductive Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,836