Onvansertib-mediated PLK1 inhibition impairs spermatogenesis in the murine testis

Onvansertib (ONV) is a selective inhibitor of polo-like kinase 1 (PLK1) and has promise in treating cancer. However, its potential effects on male reproductive function remain insufficiently characterized. In this study, male mice received clinically relevant doses of ONV by intragastric gavage for five consecutive days. Evaluations conducted on day 1, day 6, and day 35 after treatment revealed a marked increase in germ cell apoptosis accompanied by a significant reduction in epididymal sperm counts, whereas somatic cell architecture was preserved. Mechanistically, PLK1 inhibition by ONV led to a pronounced decrease in eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) phosphorylation. This disruption is likely linked to impaired meiotic centrosome maturation and aberrant spindle organization in germ cells. Collectively, these findings demonstrate that ONV preferentially induces apoptosis in germ cells via PLK1 suppression, thereby compromising spermatogenic capacity.