Flavonoid Senolytics Boost Fertility by Targeting Senescent Endometrial Cells

Endometriosis affects 10% of reproductive-age women and is a leading cause of infertility. The condition involves senescent-like endometrial stromal cells that impair decidualization—the uterine preparation process essential for embryo implantation. This study investigated whether senolytic compounds could restore normal endometrial function by eliminating these problematic senescent cells.

Researchers collected endometrial stromal cells from menstrual effluent and tested various senotherapeutics, including natural flavonoids (quercetin, fisetin, luteolin, kaempferol) and synthetic compounds (dasatinib, ABT-737, navitoclax). They measured effects on decidualization markers, cell migration, senescent cell elimination, and underlying molecular pathways.

All flavonoid senolytics dramatically improved decidualization without causing cell death. Quercetin, fisetin, and luteolin enhanced the expression of key decidualization markers while effectively eliminating senescent cells. These compounds also significantly reduced cell migration—a critical factor in endometriosis progression. Among non-flavonoids, only dasatinib showed benefits, though with notable toxicity concerns.

Mechanistic analysis revealed that effective compounds suppressed AKT signaling and upregulated p53 expression. Quercetin and fisetin uniquely reduced ERK1/2 phosphorylation, suggesting multiple pathways of action. The flavonoids' dual benefits—improving decidualization while eliminating senescent cells—position them as promising therapeutic candidates.

These findings support clinical trials testing flavonoid supplementation for endometriosis-related infertility. The ability to assess treatment effects using menstrual effluent could enable personalized monitoring of therapeutic responses.