Platycodin D Disrupts Human Sperm Function via the MAPK/p53 Pathway

Platycodin D (PD), a natural triterpenoid saponin from Platycodon grandiflorum, exhibits cytotoxic and spermatotoxic properties. However, the specific mechanisms underlying its impairment of human sperm function are not fully understood. This study was designed to focus on the effects of PD on human sperm and the mechanisms. Human spermatozoa were exposed to PD (1-100 μM). PD treatment dose-dependently reduced sperm viability, motility, penetration capacity, capacitation, and acrosome reaction. Mechanistically, PD induced a significant, dose-dependent accumulation of intracellular reactive oxygen species (ROS) and concurrently disrupted the mitochondrial membrane potential (MMP). Network pharmacology analysis predicted the mitogen-activated protein kinase (MAPK) pathway as a key mediator of the effects of PD on sperm. Experimental validation via Western blotting confirmed that PD significantly upregulated phosphorylated MAPK3 (p-MAPK3) and phosphorylated p53 (p-p53), whereas total MAPK3 was also moderately increased, to a lesser extent than p-MAPK3, and total p53 levels remained unchanged. Furthermore, PD induced the upregulation of caspase-3, an indicator of apoptosis-like pathway activation. These findings suggest that PD-induced sperm dysfunction is associated with ROS accumulation, mitochondrial depolarization, and activation of the MAPK/p53 signaling axis. Further intervention studies are warranted to establish causal relationships.