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  3. Targeting SKAP2 restores sperm motility and morphology through modulating mitochondrial organization and cytoskeletal remodeling

Targeting SKAP2 restores sperm motility and morphology through modulating mitochondrial organization and cytoskeletal remodeling

  • Signal Transduct Target Ther. 2025 Dec 24;10(1):416. doi: 10.1038/s41392-025-02513-3.
Shiming Gan # 1,  Lin Yin # 1,  Jiaming Zhou # 2,  Sisi Li # 1,  Shumin Zhou # 3,  Xiaotong Yang 2,  Rui Liu 1,  Xu Fan 4,  Yangyang Li 1,  Zhendong Yao 1,  Jingshou Chen 5,  Peiran Hu 2,  Wenjing Xiong 5,  Yuan Yuan 1,  Yujiao Wen 6,  Youjiang Li 1,  Ge Jin 7,  Jianzhong Sheng 1,  Yuzhen Gao 8,  Hefeng Huang 9 10 11 12,  Chen Zhang 13 14
Affiliations

Affiliations

  • 1 Department of Reproductive Medicine, Center for Reproductive Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China.
  • 2 Institute of Reproduction and Development, Shanghai Key Laboratory of Reproduction and Development, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.
  • 3 Department of Urology & Andrology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 4 Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, China.
  • 5 Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 6 Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 7 School of Traditional Chinese Medicine, Shenyang Medical College, Shenyang, China.
  • 8 Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. yuzhengao@zju.edu.cn.
  • 9 Department of Reproductive Medicine, Center for Reproductive Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China. huanghefg@zju.edu.cn.
  • 10 Institute of Reproduction and Development, Shanghai Key Laboratory of Reproduction and Development, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China. huanghefg@zju.edu.cn.
  • 11 Institute of Medical Genetics and Development, Key Laboratory of Reproductive Genetics (Ministry of Education) and Women's Hospital, Zhejiang University School of Medicine, Zhejiang, China. huanghefg@zju.edu.cn.
  • 12 Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China. huanghefg@zju.edu.cn.
  • 13 Institute of Reproduction and Development, Shanghai Key Laboratory of Reproduction and Development, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China. chenzhang_ired@fudan.edu.cn.
  • 14 Asian Academy of Anti-aging Research and Translational Medicine (Shenzhen), Shenzhen, China. chenzhang_ired@fudan.edu.cn.
  • # Contributed equally.
PMID: 41436426 DOI: 10.1038/s41392-025-02513-3
Abstract

Sperm motility and morphology are indispensable for sperm-egg interaction and successful fertilization. However, the RNA splicing mechanisms in an m6A-dependent manner regulating spermiogenesis-related genes remain poorly defined, and targeted therapy strategies to restore impaired sperm motility and morphology are lacking. In this study, we identify heterogeneous nuclear ribonucleoprotein R (hnRNPR) as a critical m6A-dependent splicing mediator. Pathogenic mutations in HNRNPR cause sperm motility decline, morphological abnormality, and male infertility in both humans and mice. Mechanistically, Hnrnpr mutation disrupts m6A-dependent splicing of Skap2 pre-mRNA, thus impairing cytoskeletal structure and mitochondrial organization in sperm. Consistently, specific knockout of Skap2 in male germ cells displays sperm abnormalities, which phenocopy those observed in humans and mice with Hnrnpr mutants, unveiling a functional hnRNPR-SKAP2 axis. Leveraging these insights, we developed a therapeutic strategy to restore sperm motility and morphology, relying on extracellular vesicle-mediated SKAP2 delivery to enter the efferent ductules of the testicles, which could promote sperm cytoskeletal remodeling and mitochondrial organization. Notably, the co-culture of extracellular vesicle SKAP2 with human and mouse sperms also significantly enhanced the sperm motility. Altogether, these findings identify hnRNPR as a pivotal regulator of m6A-mediated Skap2 splicing during spermiogenesis and highlight extracellular vesicle SKAP2 as a promising therapeutic target for poor sperm quality and male infertility.

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