Metformin mitigates cisplatin-induced premature ovarian insufficiency via Sirt1/Nrf2 activation

Background: Premature ovarian insufficiency (POI) occurs in young women who receive chemotherapy, with cisplatin being the known culprit. Cisplatin-induced ovarian damage associated with POI results from oxidative stress. Metformin, a widely prescribed drug for type 2 diabetes, plays an important role in the mitigation of oxidative stress. However, the precise mechanism through which metformin protects against cisplatin-induced POI remains unclear. Hence, this study aimed to investigate the protective effects of metformin against cisplatin-induced granulosa cell (GCs) damage and explore the underlying anti-oxidative stress mechanisms. Methods: In this study, an in vitro POI model was established using cisplatin-treated human GCs. Metformin pretreatment was used to assess the effects of metformin on damaged GCs. Cell viability and hormone levels were measured using CCK8 and enzyme-linked immunosorbent assay, respectively. The mechanisms of oxidative stress repair by metformin were evaluated using flow cytometry, western blot analysis, and quantitative real-time polymerase chain reaction. Results: Metformin pretreatment significantly enhanced GC viability, reduced apoptosis, decreased reactive oxygen species levels, improved mitochondrial function, and increased superoxide dismutase activity. Additionally, metformin upregulated the expression of Bcl-2, Sirt1, and Nrf2, while downregulating Bax, indicating its protective role through the activation of the Sirt1/Nrf2 signaling pathway. Conclusion: Metformin may serve as a promising therapeutic agent to prevent POI by mitigating oxidative stress and apoptosis.