Single‐Cell Insights Into Pathogenic Profile of Orchitis and SREBP2‐Associated Cholesterol Dysregulation in Spermatogenic Failure
9 affiliations
- 1Department of Urology Center For Reproductive Medicine State Key Laboratory of Female Fertility Promotion Peking University Third Hospital Beijing China
- 2State Key Laboratory of Organ Regeneration and Reconstruction Institute of Zoology Chinese Academy of Sciences Beijing China
- 3Beijing Institute for Stem Cell and Regenerative Medicine Beijing China
- 4University of the Chinese Academy of Sciences Beijing China
- 5Department of Andrology Third Affiliated Hospital of Zhengzhou University Zhengzhou Henan China
- 6State Key Laboratory of Female Fertility Promotion Center For Reproductive Medicine Department of Obstetrics and Gynecology Peking University Third Hospital Beijing China
- 7Department of Urology Peking University First Hospital Beijing China
- 8The Institution of Urology Peking University Beijing China
- 9Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center Beijing China
Abstract
Orchitis, a testicular inflammation often triggered by infection, is a major cause of male infertility due to disruption of the testicular immune microenvironment and progressive loss of germ cells. Currently, no effective or targeted therapies are available. Here, we profile 66,147 single‐cell transcriptomes from testes of orchitis patients and healthy controls, complemented by histological validation. We observe profound remodeling of testicular cell composition, with marked infiltration of CD8+ effector T cells and inflammatory macrophages, accompanied by germ cell loss. Undifferentiated spermatogonia exhibit cell‐cycle arrest, while somatic cell populations display fibrosis, apoptosis, and loss of homeostatic functions. Notably, interstitial cells show SREBP2‐ associated reprogramming of cholesterol metabolism, characterized by increased synthesis. Inhibition of SREBP2 in a mouse orchitis model improves spermatogenesis, reduces lipid accumulation, and alleviates fibrosis. These findings demonstrate that immune activation–induced SREBP2 upregulation drives cholesterol metabolic imbalance and spermatogenic failure in orchitis, offering potential therapeutic options for inflammation‐associated male infertility.
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BibTeX
@article{tang2026singlecell,
title = {{Single‐Cell Insights Into Pathogenic Profile of Orchitis and SREBP2‐Associated Cholesterol Dysregulation in Spermatogenic Failure}},
author = {Yanlin Tang and Qiaoling Jiang and Yuwen Liu and Wenxiu Zhang and Lina Cui and Xiaojian Lu and Ziyan Zhuang and Jianxing Cheng and Songzhan Gao and Yangyi Fang and Kai Hong and Jie Qiao and Xiaoyan Wang and Hui Jiang and Zhe Zhang and Jingtao Guo and Qiang Liu},
journal = {Advanced Science},
year = {2026},
month = oct,
doi = {10.1002/advs.78572},
url = {https://doi.org/10.1002/advs.78572},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Single‐Cell Insights Into Pathogenic Profile of Orchitis and SREBP2‐Associated Cholesterol Dysregulation in Spermatogenic Failure
AU - Yanlin Tang
AU - Qiaoling Jiang
AU - Yuwen Liu
AU - Wenxiu Zhang
AU - Lina Cui
AU - Xiaojian Lu
AU - Ziyan Zhuang
AU - Jianxing Cheng
AU - Songzhan Gao
AU - Yangyi Fang
AU - Kai Hong
AU - Jie Qiao
AU - Xiaoyan Wang
AU - Hui Jiang
AU - Zhe Zhang
AU - Jingtao Guo
AU - Qiang Liu
PY - 2026
DA - 2026/10/31
JO - Advanced Science
DO - 10.1002/advs.78572
UR - https://doi.org/10.1002/advs.78572
AB - Orchitis, a testicular inflammation often triggered by infection, is a major cause of male infertility due to disruption of the testicular immune microenvironment and progressive loss of germ cells. Currently, no effective or targeted therapies are available. Here, we profile 66,147 single‐cell transcriptomes from testes of orchitis patients and healthy controls, complemented by histological validation. We observe profound remodeling of testicular cell composition, with marked infiltration of CD8+ effector T cells and inflammatory macrophages, accompanied by germ cell loss. Undifferentiated spermatogonia exhibit cell‐cycle arrest, while somatic cell populations display fibrosis, apoptosis, and loss of homeostatic functions. Notably, interstitial cells show SREBP2‐ associated reprogramming of cholesterol metabolism, characterized by increased synthesis. Inhibition of SREBP2 in a mouse orchitis model improves spermatogenesis, reduces lipid accumulation, and alleviates fibrosis. These findings demonstrate that immune activation–induced SREBP2 upregulation drives cholesterol metabolic imbalance and spermatogenic failure in orchitis, offering potential therapeutic options for inflammation‐associated male infertility.
SN - 2198-3844
ER -