Nicotinamide mononucleotide alleviates the streptozotocin-mediated ferroptosis of islet β-cells via the Nrf2/GPX4 pathway.

The effects of nicotinamide mononucleotide (NMN) on streptozotocin (STZ)-induced islet β-cell dysfunction and the underlying mechanisms have not been fully elucidated. This study investigated the ameliorative effect and mechanism of NMN on islet β-cell dysfunction. NMN significantly increased the INS-1 cell viability following treatment with either STZ or erastin and effectively mitigated STZ-induced cell injury. Upon exposure to STZ, INS-1 cells exhibited significantly elevated intracellular Fe2+ levels, significantly increased reactive oxygen species (ROS) levels, and significantly decreased in the activities of superoxide dismutase (SOD) and glutathione (GSH). The levels of lipid peroxidation (LPO) and malondialdehyde (MDA) were substantially increased, and the mitochondrial membrane potential significantly decreased. Transmission electron microscopy further revealed mitochondrial shrinkage, rupture of the mitochondrial membrane, and disintegration of mitochondrial cristae. NMN markedly reduced intracellular iron accumulation in INS-1 cells treated with STZ. NMN subsequently attenuated intracellular ROS, LPO, and MDA levels while restoring GSH and SOD activities in STZ-exposed cells. Moreover, NMN restored the mitochondrial membrane potential and reversed the STZ-induced pathological changes in mitochondrial morphology. Compared with STZ treatment, ferrostatin-1 treatment significantly upregulated Nrf2 and GPX4 expression. In contrast, compared with STZ treatment, erastin treatment suppressed Nrf2 and GPX4 expression. Notably, compared with STZ or erastin treatment, cotreatment with NMN resulted in a further reduction in Keap1 expression and a significant upregulation of Nrf2 and GPX4. NMN may alleviate STZ-induced INS-1 cell ferroptosis by activating the Nrf2/GPX4 pathway, providing a theoretical basis for the treatment of diabetes mellitus.