Sperm tRNA-derived fragments: molecular mechanisms and clinical implications for paternal epigenetic inheritance

Abstract Sperm tRNA-derived fragments (tRFs) have emerged as novel regulators of paternal epigenetic inheritance. By modulating embryonic epigenetic reprogramming, transposon silencing, and intergenerational genetic programming, tRFs mediate the transgenerational transmission of paternal environmental information, extending conventional notions of genetic inheritance. This review systematically elaborates the molecular mechanisms, clinical applications, and potential interventional strategies of tRFs. Through an in-depth analysis of how tRFs regulate the epigenetic landscape during embryonic development, we highlight their applications in diagnosing and treating male infertility, as well as in preventing transgenerational diseases. This work provides new insights into interventions targeting paternal epigenetic transmission and associated disorders.