S-adenosylmethionine ameliorates spermatogenic dysfunction and sperm DNA damage via transsulfuration pathway

Male infertility is a global concern, with high sperm DNA fragmentation linked to oxidative stress. Untargeted metabolomics in 111 men revealed downregulated S-adenosylmethionine (SAM) in patients with high sperm DNA fragmentation index (DFI). In vitro experiments demonstrated that SAM supplementation effectively reduced oxidative stress-induced DNA damage of human sperm and restored motility. In vivo, SAM administration in cyclophosphamide-induced oligoasthenozoospermia mice improved testicular structure, sperm quality, and DNA integrity. SAM restored glutathione levels and upregulated the expression of key transsulfuration enzymes, cystathionine β-synthase (CBS) and cystine/glutamate transporter (xCT), thereby enhancing glutathione biosynthesis and mitigating oxidative stress. RNA sequencing and protein analysis further revealed that SAM attenuated the expression of proapoptotic markers caspase-3 and caspase-8 and reduced germ cell apoptosis. These findings suggest that SAM may alleviate spermatogenic dysfunction and DNA damage, an effect that may involve enhancement of the transsulfuration pathway and improved redox homeostasis. This offers mechanistic insights and supports further exploration of its therapeutic potential on male infertility.