Stress granule-mediated ZBP1 activation drives necroptotic cell death in non-obstructive azoospermia and testicular aging

• 成果类型: Article
• 署名作者: Lei, Hongen; Li, Dianrong; Chen, Jie; Du, Baowen; Jiang, Kaiju; Xu, Tao; Han, Hu; Fan, Weiliang; Tian, Long; Wang, Xiaodong
• 署名单位: Capital Medical University; Capital Medical University; National Institute of Biological Sciences, Beijing; Tsinghua University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14984
• DOI: 10.1073/pnas.2514837122
• 发表日期: 2025-08-14
• 关键词: phosphorylation; testis

摘要

Male infertility remains a major unmet medical challenge, with poorly defined molecular mechanisms and no effective therapies. Here, we identify a stress granule-mediated necroptotic pathway as a key driver of non-obstructive azoospermia, a severe form of male infertility marked by the loss of spermatogenesis. Environmental or physiological stress activates eIF2 alpha kinases, inducing stress granule formation and the recruitment of ZBP1 and RIPK3 into a cytoplasmic complex. This assembly triggers RIPK3 activation, MLKL phosphorylation, and necroptotic death of spermatogonia and Sertoli cells. Genetic ablation of Zbp1 or Ripka protects mice from heat-induced testicular degeneration, establishing their essential role in stress-induced testicular damage. Importantly, activation of this pathway is also observed in aged human testes, linking stress-responsive necroptosis to both pathological infertility and the broader process of reproductive aging. These findings reveal an unrecognized mechanism that couples cellular stress responses to regulated cell death in the male reproductive system.