Hydrolyzed Peptides from Pichia pastoris Improve Sperm Quality in Male Rats by Modulating the PI3K/AKT Signalling Pathway

Oxidative stress is one of the critical factors contributing to the rising prevalence of male infertility. Hydrolyzed peptides from Pichia pastoris (HPP), a major component of Pichia pastoris hydrolysate, have an underestimated impact on the male reproductive system. This study aimed to systematically evaluate the potential of HPP to improve sperm quality. Results revealed that HPP enhanced sperm quality and serum testosterone levels in rats, with no adverse impact on body weight or the genital weight index. HPP increased the diameter of seminiferous tubules, yet no significant changes were observed in the expression levels of blood-testis-barrier (BTB)-related genes (zonula occludens-1, Occludin, Connexin-43, and N-cadherin). Transcriptomics, non-target metabolomics, Western blotting, and Quantitative Real-time PCR analyses revealed that HPP-treated rats exhibited significantly upregulated antioxidant enzymes (nuclear factor erythroid-2-related factor 2 (Nrf2) and Heme Oxygenase-1 (HO-1)) expression, decreased reactive oxygen species (ROS) contents, and inhibited the PI3K/AKT signaling pathway. Moreover, we found that taurine and hypotaurine metabolism might be potential metabolic targets for improving sperm quality. Taken together, these results highlight HPP as a promising nutraceutical supplement for improving sperm quality. The antioxidant mechanism of HPP via the regulation of the PI3K/AKT signaling pathway lays a foundation for further research into nutrient-based interventions for male infertility.