Polydatin, a derivative of resveratrol, ameliorates busulfan-induced oligozoospermia in mice by inhibiting NF-κB pathway activation and suppressing ferroptosis

Polydatin (PD), a glucoside derivative of resveratrol (RES), is extracted as a monomer compound from the dried rhizome of Polygonum cuspidatum. Our laboratory synthesized PD via the biotransformation of resveratrol. To assess the reproductive protective effects of PD, an oligozoospermia mouse model was induced by administering 30 mg/kg busulfan (BUS) via intraperitoneal injection. Initially, mice were categorized into groups based on PD concentrations of 10, 50, and 100 mg/kg. Subsequently, the optimal concentration of 10 mg/kg was ascertained based on testis weight and spermatological parameters. Additionally, a 10 mg/kg resveratrol group was included as a control. The findings revealed that exposure to BUS resulted in a reduction of testicular weight, diminished spermatogenic cells and epididymal sperm counts, increased sperm deformity, disordered testicular cytoskeleton, compromised blood-testis barrier integrity, and a significant decrease in serum sex hormone levels, notably testosterone. This resulted in decreased expression of androgen receptors and other testosterone-related proteins, increased levels of malondialdehyde and reactive oxygen species, and promoted testicular ferroptosis. However, PD could successfully reverse these injuries. High-throughput sequencing data demonstrated that polydatin significantly downregulated the expression of inflammatory and metabolic genes, including PRKCQ and CARD11. These proteins are pivotal in the activation of the NF-kappa B pathway during the inflammatory response. Molecular docking studies showed that PD could interact with PRKCQ and CARD11 to reduce the level of inflammation. Additionally, PD was shown to interact with the ferroptosis-promoting gene ACSL4, modulating ferroptosis. In summary, PD facilitates the reversal of BUS-induced oligozoospermia through the mitigation of oxidative stress and inflammation, the inhibition of ferroptosis, and the modulation of hormonal levels.