Atorvastatin improves spermatogenesis in murine and in vitro human chronic orchitis models through restoring blood-testis barriers
Chronic orchitis, which stems from autoimmune responses and infections, significantly impairs the testicular niche and affects male fertility. However, there is a lack of effective therapeutic drugs. In this study, we aimed to explore whether atorvastatin can be used for the treatment of chronic orchitis and the underlying mechanism based on our previous findings and detection using the database. We utilized mouse models of chronic orchitis induced by both autoimmune and infectious causes to demonstrate that atorvastatin can markedly improve spermatogenesis and fertility. Mechanism studies through single-cell transcriptomic analysis, target gene knockdown, quantitative proteomics, and small molecule interference revealed that atorvastatin suppressed the Rac1/AP1/MMPs pathway via inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) in Sertoli cells, thereby restoring the blood-testis barrier (BTB) and spermatogenesis. More importantly, atorvastatin also re-established the expression of BTB-associated proteins and increased the germ cell numbers in cultured human testis tissues. Collectively, our study reveals the essential impact of atorvastatin in improving spermatogenesis in murine and human chronic orchitis models through restoring BTB and suggests that atorvastatin as a promising agent for the clinical treatment of chronic orchitis.
Authors
- Shaofang Ren (ORCID: https://orcid.org/0000-0001-8253-3166)
- Z. Wang (ORCID: https://orcid.org/0009-0003-2398-9405)
- Zhaoting Liu (ORCID: https://orcid.org/0000-0001-5025-4373)
- Linzi Ma (ORCID: https://orcid.org/0009-0002-7795-6695)
- Xinyan Yang (ORCID: https://orcid.org/0000-0003-2892-5534)
- Shiling Chen (ORCID: https://orcid.org/0000-0003-4473-5538)
- Kai Miao (ORCID: https://orcid.org/0000-0003-4832-3354)
- Zhaokai Yao (ORCID: https://orcid.org/0000-0001-8830-5527)
- Ke Song (ORCID: https://orcid.org/0009-0005-0672-9497)
- Qi Li (ORCID: https://orcid.org/0000-0002-9144-148X)
- Fang Luo
- Yi Zheng (ORCID: https://orcid.org/0000-0003-2630-9703)
- Xiaoyang Zhao (ORCID: https://orcid.org/0000-0003-2544-8293)
- Jiyu Chen (ORCID: https://orcid.org/0000-0003-1166-7364)
- Yongtong Zhu (ORCID: https://orcid.org/0000-0003-4827-9349)
Institutions
- Ministry of Education of the People's Republic of China (CN)
- Jinan University (CN)
- University of Macau (MO)
- National Clinical Research Center for Digestive Diseases (CN)
- Ministry of Education (RW)
- Third Affiliated Hospital of Guangzhou Medical University (CN)
- The First People's Hospital of Shunde (CN)
- Nanfang Hospital (CN)
- Guangdong-Hongkong-Macau Joint Laboratory of Collaborative Innovation for Environmental Quality (CN)
- Zhujiang Hospital (CN)
- National Clinical Research (US)
- Guangzhou Psychiatric Hospital (CN)
- Guangdong Provincial People's Hospital (CN)
- Southern Medical University (CN)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Cell Death Discovery
- Published
- 2025-11-06
- DOI
- https://doi.org/10.1038/s41420-025-02749-6
- Citations
- 3
- Primary Topic
- Sperm and Testicular Function
- Type
- article
- Field-Weighted Citation Impact
- 5.09