Redox–Genomic Crosstalk: Linking Oxidative Stress, Sperm DNA Fragmentation, and Epigenetics in Personalized Management of Male Infertility

Male infertility is increasingly recognized as a complex, multifactorial disorder that extends beyond abnormalities in conventional semen parameters. A growing body of evidence highlights oxidative stress, sperm DNA fragmentation (SDF), and epigenetic alterations as tightly interconnected mechanisms contributing to sperm dysfunction and impaired fertility. Reactive oxygen species, though vital for sperm maturation and signaling, can inflict extensive genomic and chromatin damage when their levels exceed the antioxidant capacity of the testis and seminal plasma. These redox-driven lesions not only compromise fertilization potential but may also influence embryonic development and offspring health. Clinical studies and meta-analyses consistently report that elevated SDF and redox imbalance are associated with reduced pregnancy and live birth rates, particularly in assisted reproductive technologies (ARTs). The use of testicular sperm in men with high ejaculated SDF appears to improve ART outcomes, although long-term safety data remain limited. Advances in redox and genomic diagnostics, including assays for oxidation-reduction potential, SDF, and sperm epigenetic profiling, have opened new avenues for precision-based andrology, enabling targeted antioxidant, metabolic, and surgical interventions. Nonetheless, methodological variability, lack of assay standardization, and insufficient longitudinal follow-up constrain the full clinical translation of these findings. This review synthesizes evidence linking OS, SDF, and epigenetic alterations, highlighting their mechanistic crosstalk and translational relevance in the personalized management of male infertility.