Zuogui Wan alleviates intergenerational premature ovarian insufficiency through C9-mediated complement-coagulation...

Area of Science:

• Integrative Medicine
• Reproductive Biology
• Pharmacology

Background:

• Zuogui Wan (ZGW), a traditional Chinese medicine, is used for premature ovarian insufficiency (POI) and menopausal symptoms.
• ZGW shows promise with fewer side effects than hormonal therapy, but its effect on intergenerational POI transmission is unknown.

Purpose of the Study:

• To investigate if maternal ZGW administration can prevent POI transmission to offspring.
• To elucidate the molecular mechanisms underlying ZGW's potential protective effects.

Main Methods:

• A rat model of POI induced by chronic unpredictable mild stress (CUMS) was treated with ZGW.
• Offspring (F1/F2) estrous cycles, ovarian morphology, and hormone levels were assessed.
• Multi-omics, molecular docking, simulations, and in vitro assays identified key molecular targets and pathways.

Main Results:

• ZGW improved reproductive parameters in POI offspring and tended to normalize hormone levels.
• Multi-omics analysis identified C9-driven complement signaling (C9/ITGAM/KNG1) as a key pathway.
• Quercetin in ZGW bound C9, and C9 inhibition affected ZGW's protective effects in vitro.

Conclusions:

• ZGW alleviates intergenerational POI transmission through the C9-mediated complement-coagulation cascade.
• This study provides insights into managing hereditary ovarian disorders using traditional Chinese medicine.