Melatonin Inhibits the Ferroptosis Pathway in Rat Bone Marrow Mesenchymal Stem Cells by Activating the PI3K/AKT/mTOR Signaling Axis to Attenuate Steroid‐Induced Osteoporosis

Abstract

Steroid‐induced osteoporosis (SIOP) is a form of secondary osteoporosis, but its specific mechanism remains unclear. Glucocorticoid (GC‐)‐induced death of osteoblasts and bone marrow mesenchymal stem cells (BMSCs) is an important factor in SIOP. Ferroptosis is an iron‐dependent type of programmed cell death and can be induced by many factors. Herein, we aimed to explore whether GCs cause ferroptosis of BMSCs, identify pathways as possible therapeutic targets, and determine the underlying mechanisms of action. In this study, we used high‐dose dexamethasone (DEX) to observe whether GCs induce ferroptosis of BMSCs. Additionally, we established a rat SIOP model and then assessed whether melatonin (MT) could inhibit the ferroptosis pathway to provide early protection against GC‐induced SIOP and investigated the signaling pathways involved. In vitro experiments confirmed that DEX induces ferroptosis in BMSCs. MT significantly alleviates GC‐induced ferroptosis of BMSCs. Pathway analysis showed that MT ameliorates ferroptosis by activating the phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) axis. MT upregulates the expression of PI3K, which is an important regulator of ferroptosis resistance. PI3K activators mimic the antiferroptotic effect of MT, but when the PI3K pathway is blocked, the effect of MT is weakened. Using in vivo experiments, we confirmed the in vitro results and observed that MT can obviously protect against SIOP induced by GC. Notably, even after the initiation of GC‐induced ferroptosis, MT can confer protection against SIOP. Our research confirms that GC‐induced ferroptosis is closely related to SIOP. MT can inhibit ferroptosis by activating the PI3K/AKT/mTOR signaling pathway, thereby inhibiting the occurrence of SIOP. Therefore, MT may be a novel agent for preventing and treating SIOP.