Ionizing radiation-induced disruption of Rela-Bclaf1-spliceosome regulatory axis in primary spermatocytes causing spermatogenesis dysfunction

  • Cell Commun Signal. 2025 Jan 31;23(1):58. doi: 10.1186/s12964-025-02067-5.
Hongjian Zhou  #  1 ,  Zhipeng Xu  #  2 ,  Chun Jiang  1 ,  Qiuyue Wu  1 ,  Chuanyue Zhang  1 ,  Zhenyu Liu  1 ,  Xiaoxue Zhang  1 ,  Weiwei Li  1 ,  Yujia Pang  1 ,  Jing Zhang  1 ,  Wenju Pan  1 ,  Min Chen  1 ,  Xinyi Xia  3  4
Affiliations
  • 1. Institute of Laboratory Medicine, Jinling Hospital, First School of Clinical Medicine, Nanjing University School of Medicine, Southern Medical University, Zhongshan East Road 305, Nanjing, Jiangsu, 210002, China.
  • 2. Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, 210008, China.
  • 3. Institute of Laboratory Medicine, Jinling Hospital, First School of Clinical Medicine, Nanjing University School of Medicine, Southern Medical University, Zhongshan East Road 305, Nanjing, Jiangsu, 210002, China. [email protected].
  • 4. State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu, 210093, China. [email protected].
  • # Contributed equally.
PMID: 39891142 DOI: 10.1186/s12964-025-02067-5
Abstract

Introduction: Ionizing radiation (IR) poses a significant threat to male fertility by inducing substantial changes in the testis, yet the mechanisms underlying IR-induced spermatogenesis disorders remain poorly understood, necessitating the development of more effective radioprotective agents.

Methods: We employed Bulk RNA-seq and single-cell RNA-seq (scRNA-seq) on Balb/c mice testes models following IR exposure to assess cellular and transcriptional alterations. Histological examination, sperm concentration and motility analysis, Western blotting (WB), and reverse transcription quantitative PCR (RT-qPCR) were used to evaluate testicular injury. The therapeutic potential of NF-κB agonists was investigated in an IR-induced spermatogenesis disorder model.

Results: A 6 Gy IR dose induced spermatogenesis disorder and suppressed the spliceosome pathway, predominantly affecting the cell abundance of spermatogonia and primary spermatocytes. Bioinformatics analysis revealed that IR induced splicing disorders in differentiation-related genes, thereby impairing the differentiation ability of primary spermatocytes. Mechanistically, This IR-induced disruption was linked to IR-induced inhibition of NF-κB/Rela and Bclaf1 activity. Notably, NF-κB agonists were found to ameliorate this damage via upregulating Bclaf1 and spliceosome-related genes expression, thereby normalizing splicing patterns and rescuing IR-induced spermatogenesis disorders.

Conclusion: This study reveals a novel IR-mediated Rela-Bclaf1-spliceosome regulatory axis in primary spermatocytes and propose Rela as a potential drug target for mitigating IR-induced spermatogenesis disorders. This study not only provides new insights for further research into IR-induced damage and spermatogenic disorders caused by Other factors, but also offers potential therapeutic strategies for developing radioprotective agents in Cancer radiotherapy.

Keywords
Bclaf1; Ionizing radiation; NF-κB agonist; Rela; Spermatogenesis dysfunction; Spliceosome; scRNA-seq.
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