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 eIF2 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.