GPX4-Mediated Inhibition of Ferroptosis by Sodium Selenite Ameliorates Bone Metabolic Disorders in Ovariectomized Mice.

Postmenopausal osteoporosis (PMOP) and its associated fracture complications have emerged as pressing public health challenges due to rapidly accelerating global population ageing. The functional decline of bone marrow mesenchymal stem cells (BMSCs) under elevated oxidative stress is a recognised pathogenic cornerstone of PMOP, positioning redox imbalance as a critical therapeutic node. Here, we establish that sodium selenite (Na2SeO3) robustly counters oxidative insults in BMSCs, thereby restoring and enhancing their osteogenic lineage commitment. Furthermore, RNA sequencing analysis indicated that ferroptosis may be mechanistically associated with the underlying cellular responses. Ferroptosis is critically mediated by glutathione peroxidase 4 (GPX4), a selenoenzyme that functions as its principal enzymatic suppressor. Silencing GPX4 in BMSCs markedly reduced their osteogenic capacity and simultaneously upregulated ferroptotic protein expression. Notably, this impairment was not reversed by Na2SeO3 administration under conditions of GPX4 suppression. These findings suggest that Na2SeO3 enhances osteogenic differentiation primarily by upregulating GPX4 expression, thereby inhibiting ferroptosis. Thus, we have established Na2SeO3 as a potential therapeutic strategy for PMOP by identifying a previously unrecognised molecular axis through which selenium regulates bone metabolic homeostasis.