Cell-resolved genetic risk reveals hyperandrogenism-associated immune and metabolic rewiring in the PMOS follicular microenvironment.
7 affiliations
- 1Department of Traditional Chinese Gynecology, the First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China.
- 2Department of Assisted Reproduction, the First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China.
- 3Guang' Anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China.
- 4Department of Reproductive Immunology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China. [email protected].
- 5Department of Traditional Chinese Gynecology, the First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China. [email protected].
- 6Academy of Military Medical Sciences, Beijing, 100850, China. [email protected].
- 7Department of Traditional Chinese Gynecology, the First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China. [email protected].
Abstract
Background
Polyendocrine metabolic ovarian syndrome (PMOS) is a leading cause of anovulatory infertility. Although follicular developmental arrest is a defining feature of PMOS, the cell-type-specific mechanisms linking genetic susceptibility, endocrine imbalance and follicular microenvironmental dysfunction remain incompletely understood, particularly across clinical subtypes.Methods
We performed single-cell RNA sequencing of preovulatory follicular-fluid cells from healthy controls and women with uncomplicated PMOS, hyperandrogenic PMOS and metformin-treated insulin-resistant PMOS. We integrated these data with GWAS-derived disease relevance scores and ovarian chromatin-accessibility annotations to map genetic risk to follicular cell populations and regulatory programmes. Ligand-receptor analyses were used to infer intercellular communication networks. Transcriptomic metabolic findings were further assessed by follicular-fluid metabolic and steroid-hormone measurements, DHT-treated granulosa-cell functional assays, and reanalysis of a DHEA-induced mouse PMOS-like ovarian dataset.Results
We generated a single-cell atlas of the PMOS follicular microenvironment comprising 220,983 high-quality cells. Granulosa cells showed the strongest enrichment of PMOS-related genetic risk, with regulatory-genetic support from ovarian snATAC-seq integration. Among granulosa cell states, a GC2_CYP19A1⁺ population was preferentially associated with hyperandrogenic PMOS and displayed a transcriptional programme characterized by steroidogenic remodelling coupled to reduced energy-metabolic activity. Biochemical profiling supported this endocrine-metabolic imbalance, showing increased follicular-fluid androstenedione (ASD) and estrone, reduced estradiol and E2/ASD ratio, decreased ATP, citrate and fumarate hydratase activity, and increased lactate and β-hydroxybutyrate. Prolonged DHT exposure impaired granulosa-cell mitochondrial respiration, ATP production and mitochondrial membrane potential. In parallel, PMOS subtypes showed immune remodelling and altered ligand-receptor signalling, with hyperandrogenic PMOS associated with increased inflammatory signalling and reduced homeostatic or tissue-repair pathways. Reanalysis of a DHEA-induced mouse ovarian dataset provided supportive evidence for androgen-associated steroidogenic pathway perturbation.Conclusions
This study provides a cell-resolved framework linking PMOS genetic susceptibility to endocrine-metabolic and immune remodelling in the preovulatory follicular microenvironment. The identification of a hyperandrogen-associated GC2_CYP19A1⁺ state highlights a candidate cellular programme in which steroidogenic imbalance is coupled to impaired granulosa-cell bioenergetics. These findings provide a resource for future validation and may inform microenvironment-guided stratification of PMOS and the development of strategies aimed at restoring follicular function.
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BibTeX
@article{li2026cellresolved,
title = {{Cell-resolved genetic risk reveals hyperandrogenism-associated immune and metabolic rewiring in the PMOS follicular microenvironment.}},
author = {Yangshuo Li and Di Song and Dongxue Zheng and Xianglin Li and Qianqian Zhao and Yan Liao and Jie Ding and Xiaolan Liang and Mingqing Li and Chaoqin Yu and Zhexin Ni and Jin Yu},
journal = {Genome medicine},
year = {2026},
month = jul,
doi = {10.1186/s13073-026-01734-7},
url = {https://europepmc.org/article/MED/42894247},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Cell-resolved genetic risk reveals hyperandrogenism-associated immune and metabolic rewiring in the PMOS follicular microenvironment.
AU - Yangshuo Li
AU - Di Song
AU - Dongxue Zheng
AU - Xianglin Li
AU - Qianqian Zhao
AU - Yan Liao
AU - Jie Ding
AU - Xiaolan Liang
AU - Mingqing Li
AU - Chaoqin Yu
AU - Zhexin Ni
AU - Jin Yu
PY - 2026
DA - 2026/07/01
JO - Genome medicine
DO - 10.1186/s13073-026-01734-7
UR - https://europepmc.org/article/MED/42894247
AB - Background Polyendocrine metabolic ovarian syndrome (PMOS) is a leading cause of anovulatory infertility. Although follicular developmental arrest is a defining feature of PMOS, the cell-type-specific mechanisms linking genetic susceptibility, endocrine imbalance and follicular microenvironmental dysfunction remain incompletely understood, particularly across clinical subtypes.Methods We performed single-cell RNA sequencing of preovulatory follicular-fluid cells from healthy controls and women with uncomplicated PMOS, hyperandrogenic PMOS and metformin-treated insulin-resistant PMOS. We integrated these data with GWAS-derived disease relevance scores and ovarian chromatin-accessibility annotations to map genetic risk to follicular cell populations and regulatory programmes. Ligand-receptor analyses were used to infer intercellular communication networks. Transcriptomic metabolic findings were further assessed by follicular-fluid metabolic and steroid-hormone measurements, DHT-treated granulosa-cell functional assays, and reanalysis of a DHEA-induced mouse PMOS-like ovarian dataset.Results We generated a single-cell atlas of the PMOS follicular microenvironment comprising 220,983 high-quality cells. Granulosa cells showed the strongest enrichment of PMOS-related genetic risk, with regulatory-genetic support from ovarian snATAC-seq integration. Among granulosa cell states, a GC2_CYP19A1⁺ population was preferentially associated with hyperandrogenic PMOS and displayed a transcriptional programme characterized by steroidogenic remodelling coupled to reduced energy-metabolic activity. Biochemical profiling supported this endocrine-metabolic imbalance, showing increased follicular-fluid androstenedione (ASD) and estrone, reduced estradiol and E2/ASD ratio, decreased ATP, citrate and fumarate hydratase activity, and increased lactate and β-hydroxybutyrate. Prolonged DHT exposure impaired granulosa-cell mitochondrial respiration, ATP production and mitochondrial membrane potential. In parallel, PMOS subtypes showed immune remodelling and altered ligand-receptor signalling, with hyperandrogenic PMOS associated with increased inflammatory signalling and reduced homeostatic or tissue-repair pathways. Reanalysis of a DHEA-induced mouse ovarian dataset provided supportive evidence for androgen-associated steroidogenic pathway perturbation.Conclusions This study provides a cell-resolved framework linking PMOS genetic susceptibility to endocrine-metabolic and immune remodelling in the preovulatory follicular microenvironment. The identification of a hyperandrogen-associated GC2_CYP19A1⁺ state highlights a candidate cellular programme in which steroidogenic imbalance is coupled to impaired granulosa-cell bioenergetics. These findings provide a resource for future validation and may inform microenvironment-guided stratification of PMOS and the development of strategies aimed at restoring follicular function.
SN - 1756-994X
ER -