Seminal ubiquitin as an independent predictor of severe sperm damage and ICSI outcomes: evidence for a redox-proteostasis axis in male infertility†.

Oxidative stress plays a central role in male infertility by inducing lipid peroxidation, DNA damage, and activation of sperm quality control mechanisms. However, the integrated relationship between oxidative stress, genomic damage, cellular stress response, and ubiquitin-mediated sperm elimination remains unclear. This study evaluated seminal plasma levels of malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), clusterin, and ubiquitin across distinct infertility phenotypes and assessed their predictive value. A total of 132 men were stratified into four groups based on sperm morphology and DNA fragmentation index (DFI): fertile normozoospermic, isolated teratozoospermia, isolated high DFI, and combined structural-genomic impairment. Biomarker concentrations were determined using enzyme-linked immunosorbent assay. All biomarkers increased progressively across infertility phenotypes (P < 0.001). Ubiquitin showed the strongest correlation with DFI (r = 0.71, P < 0.001) and remained the only independent predictor in multivariate linear regression (β = 0.41, P = 0.002). It also independently predicted the severe combined phenotype in logistic regression (OR = 1.19, 95% CI: 1.07-1.33, P = 0.001), with high discriminative performance (AUC = 0.88). In intracytoplasmic sperm injection (ICSI) cycles, elevated seminal ubiquitin levels were independently associated with reduced clinical pregnancy rates (adjusted OR = 0.74, P = 0.001) and improved model discrimination beyond female age and DFI (AUC 0.78-0.86). These findings support a redox-genomic damage-proteostasis axis in male infertility and identify ubiquitin as an integrative biomarker of severe sperm damage with clinical relevance beyond conventional semen analysis.