Trigonelline activates NRF2 and awakens dormant ovarian follicles to promote pregnancy in aging mice

Aging ovaries exhibit increased oxidative stress, contributing to infertility through cellular and hormonal changes. Nuclear factor E2-related factor 2 (NRF2), a key transcription factor, regulates antioxidant responses. This study investigates NRF2 in dormant (primordial) ovarian follicles to determine if NRF2 activation accounts for primordial follicle activation. We show that trigonelline (TRG) transiently activates NRF2, promoting primordial follicle activation in the non-hormonal phase of follicle development. Indeed, TRG enhances egg quality in aged mice. In human ovarian tissues, TRG increased activation of primordial follicles, resulting in more primary and secondary follicles. Mechanistically, TRG induces NRF2 nuclear translocation and upregulates NRF2-responsive genes, including <i>Egf</i>. Elevated epidermal growth factor (EGF) levels activate EGF receptor (EGFR), increasing protein kinase B (AKT) phosphorylation, which leads to FOXO3A nuclear extrusion and primordial follicle activation. These findings demonstrate that transient NRF2 activation is sufficient to initiate primordial follicle activation and follicle growth and development.