Silencing of METTL16 protects granulosa cells from the cisplatin-induced ferroptosis in premature ovarian failure

Abstract Premature ovarian failure (POF) and insufficiency induced by cisplatin are common complications associated with gynecological diseases. This study aims to investigate the role of N 6 -methyladenosine (m 6 A) methyltransferase METTL16 in cisplatin-induced ovarian granulosa cells ferroptosis. In cisplatin-treated ovarian tissue, the level of METTL16 was significantly elevated. Furthermore, METTL16 was also upregulated in cisplatin-stimulated granulosa cells. Functionally, silencing METTL16 inhibited iron accumulation and lipid peroxidation, while alleviating mitochondrial injury. Mechanistically, METTL16 was found to target NRF2, negatively regulating its RNA stability, and YTHDF2 facilitated the degradation of NRF2 mRNA. In summary, the METTL16/YTHDF2/NRF2 axis regulates ferroptosis in cisplatin-stimulated granulosa cells in POF. This study suggests that METTL16 may serve as a promising immunotherapeutic target for POF.