USP2 Attenuates Spermatogenic Cell Apoptosis Via PINK1/Parkin-Dependent Mitophagy in Varicocoele: A Functional Study

  • Andrology. 2026 Apr 10. doi: 10.1111/andr.70230.
Rui-Jie Yao  1  2 ,  Hong Xiao  1  2 ,  Jun-Hang Zheng  1  2 ,  Bin Lin  3  4 ,  Shi-Jie Liao  1  2 ,  Hao-Han He  1  2 ,  Ning Xu  3  4 ,  Hui-Liang Zhou  1  2
Affiliations
  • 1. Department of Andrology and Sexual Medicine, Urology Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
  • 2. Department of Andrology and Sexual Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
  • 3. Department of Urology, Urology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
  • 4. Department of Urology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
PMID: 41960601 DOI: 10.1111/andr.70230
Abstract

Background: Varicocoele is a major cause of male infertility, yet its underlying molecular mechanisms and determinants of surgical efficacy remain unclear.

Objective: This study aimed to identify key proteins involved in varicocoele-related infertility and to investigate the expression and functional role of ubiquitin-specific peptidase 2 in spermatozoa and spermatogenic cells.

Methods: Ubiquitin-specific peptidase 2 expression in spermatozoa from varicocoele patients was analyzed before and after varicocelectomy by Western blotting. In vitro, ubiquitin-specific peptidase 2 was overexpressed or silenced in mouse GC-2 spermatocyte cells to assess mitochondrial Autophagy (PINK1/Parkin pathway), autophagic flux, Apoptosis, and Reactive Oxygen Species. In vivo, a left-sided varicocoele rat model was established, and ubiquitin-specific peptidase 2 activity was inhibited by intratesticular injection of ML364. Testicular histopathology and sperm motility were evaluated.

Results: Ubiquitin-specific peptidase 2 protein expression was significantly reduced in spermatozoa after varicocelectomy. Ubiquitin-specific peptidase 2 overexpression enhanced PINK1/Parkin-mediated mitochondrial Autophagy and protected spermatogenic cells from Apoptosis, whereas ubiquitin-specific peptidase 2 knockdown impaired mitochondrial Autophagy and increased cell Apoptosis. In varicocoele rats, ubiquitin-specific peptidase 2 inhibition aggravated seminiferous tubule damage, reduced spermatogenic cell density, and impaired sperm motility. In human spermatozoa, ML364 treatment significantly decreased progressive motility without affecting sperm concentration.

Conclusion: Ubiquitin-specific peptidase 2 is essential for maintaining mitochondrial quality control and spermatogenic cell survival in varicocoele by regulating PINK1/Parkin-mediated Autophagy and oxidative stress, highlighting its potential as a biomarker and therapeutic target for varicocoele-related male infertility.

Keywords
mitochondrial autophagy; oxidative stress; spermatogenesis; ubiquitin‐specific peptidase 2; varicocoele.
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