Jinhong Li, Tiao Xie, Chang Lin, Danhong Peng, Qin Shi, Can Zhu
Polygonum multiflorum Thunb. is a widely consumed functional food and dietary supplement in East Asia. However, whether its bioactive component, 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG), can alleviate premature ovarian insufficiency (POI) remains unknown. This study aimed to investigate whether TSG administration alleviates POI in association with suppression of ZBP1/PANoptosis signaling. A tripterygium glycoside-induced POI rat model was treated with TSG via intraperitoneal injection. Ovarian function was assessed via estrous cycles, hormone assays (FSH, E2, AMH), and histopathology. The formation of the ZBP1/PANoptosome and key executioners of PANoptosis were analyzed by immunofluorescence and Western blot. In triptolide-injured KGN granulosa cells, TSG's effects were measured by assessing cell viability, apoptosis, lactate dehydrogenase (LDH) release, and PANoptosis activation with or without ZBP1 overexpression. TSG significantly restored estrous cyclicity, improved hormone profiles, and preserved follicular reserve in POI rats. At the molecular level, TSG was associated with reduced ZBP1/PANoptosome formation and downstream executioners (e.g., cleaved Caspase-3, N-GSDMD, p-MLKL). In cells, TSG mitigated cellular injury. Crucially, while ZBP1 overexpression aggravated damage and amplified PANoptosis signaling, TSG co-treatment significantly reversed these effects, indicating that ZBP1/PANoptosis signaling may be associated with the protective effects of TSG against POI. In conclusion, TSG mitigates POI in association with the suppression of ZBP1/PANoptosis, thereby enhancing the mechanistic understanding of POI pathogenesis and positioning TSG as a candidate for further investigation.