Metformin protects ovarian granulosa cells in chemotherapy-induced premature ovarian failure mice through AMPK/PPAR-γ/SIRT1 pathway

The incidence of premature ovarian failure (POF) is progressively escalating, with chemotherapy drugs identified as a significant contributing factor. Our study demonstrates that chemotherapy drugs can induce abnormal inflammation and oxidative stress within the ovary, resulting in damage to granulosa cells (GCs), which may be a significant cause of POF. Furthermore, numerous studies have reported Metformin (MET) has various beneficial effects, including anti-aging, anti-oxidative stress, and anti-inflammatory. Hence, the objective of this study is to investigate whether MET can be utilized for the treatment of chemotherapy-induced ovarian inflammation and the improvement of premature aging. Our vivo experiments conducted on animal models indicate that oral administration of MET ameliorates chemotherapy-induced ovarian damage and alleviates hormonal disruption in mice with POF by reducing inflammatory and oxidative stress-related harm. In our in vitro experiments, we aimed to simulate the inflammatory condition present within the ovary by indirectly co-culturing primary GCs with M1 macrophages. We observed injury to GCs caused by M1 macrophage supernatants was mitigated by treatment with MET. To validate the potential pathways involved in the action of MET, we observed that MET ameliorated GCs damage induced by M1 macrophages, possibly through the activation of the AMPK/PPAR-γ/SIRT1 pathway.