Grtp1 Safeguards Against Paternal Reproductive Aging and Intergenerational Behavioral Deficits by Preserving Redox...

Oxidative stress is a primary mediator of male reproductive decline and offspring behavioral abnormalities. Unlike females, males exhibit enhanced antioxidant capacity and sustained fertility, but the mechanism is unclear. Here, using single-cell transcriptomics and cross-sex comparisons, we identify Grtp1 as critical for counteracting male reproductive aging and protecting offspring from behavioral deficits by preserving germline redox homeostasis and sperm DNA methylation stability. Grtp1 ablation recapitulates aging phenotypes, including oxidative stress, mitochondrial dysfunction, impaired spermatogenesis, and offspring anxiety and social deficits. Mechanistically, GRTP1 interacts with PRDX1/4 and TXN to maintain germline redox balance. Notably, growth hormone treatment in aged males rescues germline redox homeostasis, restores abnormal sperm DNA methylation and quality, and ameliorates offspring behavioral deficits in a Grtp1-dependent manner. Our study establishes GRTP1 as a key redox safeguard against male germline aging and highlights the GH-GRTP1 axis as a promising therapeutic target for age-related reproductive and intergenerational behavioral deficit.