Stress Granule Formation Drives ZBP1-dependent Necroptosis in Non-obstructive Azoospermia and Aging testes

Abstract Male infertility and age-related reproductive decline remain major unmet medical challenges, with limited understanding of the underlying mechanisms. Here, we identify a stress granule–driven necroptosis pathway involving ZBP1 and RIPK3 as a central driver of non-obstructive azoospermia (NOA) , a severe form of male infertility marked by loss of spermatogenesis. We show that heat stress or environmental insults activate eIF2α kinases , inducing stress granules that recruit ZBP1 and RIPK3 to form a signaling complex. This leads to RIPK3 activation , MLKL phosphorylation , and necroptotic death of spermatogonia and Sertoli cells . Genetic ablation of Zbp1 or Ripk3 protects mice from heat-induced testicular atrophy , highlighting their essential role in testicular cell death. Notably , this same necroptosis pathway is also activated in aged human testes , suggesting a shared mechanism driving both male infertility and age-related testicular degeneration.