Dexamethasone induces ferroptosis via P53/SLC7A11/GPX4 pathway in glucocorticoid-induced osteonecrosis of the femoral head

Recently, ferroptosis as new regulatory necrosis has attracted the scientific community. However, the study focused on the effect of ferroptosis on osteocytes in steroid (glucocorticoid)-induced osteonecrosis of the femoral head (SONFH) is still scarce. In this study, we use bioinformatic analysis to screen out differentially expressed genes (DEGs) in osteoblasts that treated by dexamethasone (Dex) in GSE10311 and found these DEGs are enriched in the ferroptosis signaling pathway. The results in vitro experiments show that Dex can induce MC3T3-E1 cells ferroptosis by down-regulating SLC7A11. Specifically, Dex inhibits the expression of SLC7A11/GPX4, decreases the activity of the intracellular antioxidant system such as intracellular glutathione (GSH), while increasing Malondialdehyde (MDA), reactive oxygen species (ROS), and lipid ROS, and reduces the volume of mitochondria, the mitochondrial ridges and a series of obvious ferroptosis features. The overexpression of SLC7A11 and the use of ferroptosis inhibitor (Fer-1) can reverse the Dex-induced MC3T3 ferroptosis. Dex can induce an increase in the expression of p53 and knocking down the expression of p53 by small interfering ribonucleic acid (siRNA) can reverse the suppression of SLC7A11 and GPX4 expression in MC3T3-E1 and MOLY4 cells, thereby reducing the production of ferroptosis. Thus, this study demonstrated that Dex induces MC3T3-E1cells ferroptosis via p53/SLC7A11/GPX4 pathway. The present finding offers novel insight to understand the underlying molecular mechanisms for glucocorticoid-induced osteonecrosis. Moreover, the suppression of ferroptosis may be a novel and promising treatment option for SONFH.