Dexamethasone Induces Ferroptosis in MC3T3-E1 Cells by Promoting DNMT3a-Mediated Sirt1 DNA Hypermethylation in the Context of Steroid-Induced Osteonecrosis of the Femoral Head

• • Dex treatment significantly downregulated Sirt1 expression in MC3T3-E1 cells, with a concomitant increase in ferroptosis markers; this identifies Sirt1 as a critical negative regulator of ferroptosis in osteoblasts, offering a potential target for preventing glucocorticoid-induced bone loss. • • Overexpression of Sirt1 increased the levels of ferroptosis-related proteins SLC7A11 and GPX4 following Dex exposure, indicating that Sirt1 exerts its protective effect by upregulating these antioxidant defense proteins, which could be leveraged in therapeutic strategies. • • Dex promotes hypermethylation of the Sirt1 promoter via DNMT3a, establishing a direct epigenetic mechanism for Sirt1 suppression; this implicates DNMT3a as a druggable target to block the deleterious effects of glucocorticoids on bone. • • The study was limited to in vitro experiments; in vivo validation using Sirt1 knockout or transgenic animal models is necessary to confirm the pathophysiological relevance and to assess the translational potential of targeting the DNMT3a-Sirt1-ferroptosis axis.