Intraovarian injection of securinine stimulates the growth of small ovarian follicles by reducing stromal suppression

The lack of hormone-responsive follicles is a major challenge in treating infertility/subfertility in women with premature ovarian insufficiency or diminished ovarian reserve. In this study, we demonstrate that securinine, a neurological drug, can be repurposed to promote small follicle growth. In aged mice, intraovarian injection of securinine significantly enhances follicular development and improves fertility, yielding healthy offspring. Mechanistically, single-cell RNA sequencing reveals that securinine promotes follicular development by alleviating the negative regulation from the stromal extracellular matrix on granulosa cells. Furthermore, intraovarian injection of securinine in aged cynomolgus macaques effectively stimulates the development of small follicles into large antral follicles. Our findings highlight securinine as a promising candidate for ultrasound-guided ovarian injection for treating infertility/subfertility in women with premature ovarian insufficiency, diminished ovarian reserve, or advanced maternal age. As a small molecule drug, intraovarian securinine injection offers clinical advantages that avoid complex preparation procedures required for platelet-rich plasma or stem cell-based therapies.