biostudies-literatureLei HMOST | Dream Project of Ministry of Science and Technology of the People's Republic of China (Dream Project of MOST of China)e2514837122https://www.ebi.ac.uk/biostudies/studies/S-EPMC12377765biostudies-literatureUnknown122(33)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 <i>Zbp1</i> or <i>Ripk3</i> protects mice from heat-induced testicular degeneration, establishing their essential role in stress-induced testicular damage. Importantly, activation of tProceedings of the National Academy of Sciences of the United States of AmericaStress granule-mediated ZBP1 activation drives necroptotic cell death in non-obstructive azoospermia and testicular aging.PMC12377765n/aJiang KFan WTian LDu BLi DChen JLei HXu THan HWang XfalseStress granule-mediated ZBP1 activation drives necroptotic cell death in non-obstructive azoospermia and testicular aging.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 <i>Zbp1</i> or <i>Ripk3</i> protects mice from heat-induced testicular degeneration, establishing their essential role in stress-induced testicular damage. Importantly, activation of t2025-01-01T00:00:00Z2025 Aug2026-05-10T01:51:30.169Z2026-04-08T01:25:43.042ZS-EPMC123777654081146310.1073/pnas.2514837122