Swertiamarin Rescues 3-NPA-induced Defective Follicular Development via Modulating the NRF2/HO-1 Signaling Pathway in Granulosa Cells

The normal development of ovarian follicles, characterized by oocyte growth and granulosa cell proliferation, is essential for maintaining female fertility. Elevated oxidative stress, resulting from various in vivo and in vitro factors, significantly impairs follicular development, ovulation, and overall female fertility. Swertiamarin, a naturally occurring iridoid terpenoid compound, exhibits multiple beneficial properties, including anti-hyperlipidemic, anti-diabetic, and antioxidant effects. This study investigates the impact of Swertiamarin on follicular development impairment induced by oxidative stress, using the commonly applied oxidant 3-nitrophthalic acid (3-NPA) in a murine model. Our findings indicate that Swertiamarin administration mitigates the adverse effects of 3-NPA on follicular development and ovulation. Further analyses reveal that Swertiamarin treatment partially enhances granulosa cell proliferation and inhibits apoptosis under oxidative stress in vivo and in vitro. Moreover, Swertiamarin reduces oxidative stress in ovaries and granulosa cells exposed to 3-NPA. The expression levels of key members of the NRF2/HO-1 signaling pathway, including nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (Ho-1), and superoxide dismutase 1 (Sod1), were upregulated following Swertiamarin supplementation in 3-NPA-treated ovaries and granulosa cells. In conclusion, the present study demonstrates that Swertiamarin can partially restore defective follicular development induced by oxidative stress via modulating the NRF2/HO-1 pathway in granulosa cells. These findings provide novel insights into the potential application of Swertiamarin in enhancing female reproductive health and offer a promising strategy for addressing reproductive damage caused by oxidative stress.