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Stress granule-mediated ZBP1 activation drives necroptotic cell death in non-obstructive azoospermia and testicular
Hongen Lei1,2, Dianrong Li3, Jie Chen3
1Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
Abstract:
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 eIF2α 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 Ripk3 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.
Insights
A newly identified necroptotic pathway driven by stress granules is a key cause of male infertility. Blocking this pathway protects against testicular damage and may offer new therapies for infertility and reproductive aging.
Area of Science:
- Reproductive Biology
- Cell Death Mechanisms
- Molecular Endocrinology
Background:
- Male infertility, particularly non-obstructive azoospermia, presents a significant clinical challenge due to poorly understood molecular underpinnings.
- Current therapeutic options for male infertility are limited, highlighting the need for novel mechanistic insights.
Purpose of the Study:
- To elucidate the molecular mechanisms driving non-obstructive azoospermia and identify potential therapeutic targets.
- To investigate the role of stress responses and regulated cell death pathways in male infertility and reproductive aging.
Main Methods:
- Investigated stress granule formation and necroptosis signaling in mouse models of testicular stress.
- Utilized genetic ablation of key necroptosis pathway components (ZBP1, RIPK3) to assess their role in testicular damage.
- Examined the activation of this pathway in aged human testes.
Main Results:
- Identified a stress granule-mediated necroptotic pathway involving ZBP1 and RIPK3 as a critical driver of spermatogenesis loss.
- Demonstrated that genetic deletion of ZBP1 or RIPK3 confers protection against heat-induced testicular degeneration in mice.
- Observed activation of this necroptotic pathway in aged human testes, linking it to infertility and reproductive aging.
Conclusions:
- A stress granule-mediated necroptotic pathway is a key contributor to male infertility and testicular aging.
- Targeting ZBP1-RIPK3-mediated necroptosis presents a potential therapeutic strategy for male infertility.
- This pathway represents an unrecognized link between cellular stress, regulated cell death, and male reproductive health.
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