Steap4 Promotes Senile Osteoporosis via Fe 2+ ‐ROS/C/EBPβ Feedback‐Driven Ferroptosis and Adipogenesis in Senescent BMSCs

Abstract Senile osteoporosis (SOP) is a systemic bone disease characterized by increased susceptibility to fractures. In this study, it is found that senescent bone marrow mesenchymal stem cells (BMSCs) exhibit increased sensitivity to ferroptosis, a phenomenon associated with Steap4, a nicotinamide adenine dinucleotide phosphate hydrogen (NADPH)‐dependent metalloreductase that reduces Fe 3+ to Fe 2+ . Therefore, it is aimed to innovatively elucidate how Steap4 affects ferroptosis in senescent BMSCs. These findings indicate that Steap4 promotes intracellular Fe 2+ accumulation and elevates reactive oxygen species (ROS) levels, collectively driving the upregulation of CCAAT/enhancer binding protein beta (C/EBPβ) expression. Interestingly, a functional C/EBPβ binding site is identified within the Steap4 promoter region. Mechanistically, knockdown studies demonstrated that C/EBPβ depletion attenuated Steap4 expression, whereas C/EBPβ overexpression conversely upregulated Steap4 levels. These regulatory processes establish a self‐amplifying Steap4/Fe 2+ ‐ROS/C/EBPβ positive feedback loop. Notably, a large number of adipocytes are also observed in the bone marrow of aged mice. Knockdown of Steap4 and C/EBPβ suppressed the differentiation of BMSCs into adipocytes. Knockdown of Steap4 or deferoxamine (DFO) treatment in animal experiments effectively relieves SOP. In conclusion, Steap4 accelerates the onset of ferroptosis in senescent BMSCs and promotes their differentiation to adipocytes through the Steap4/Fe 2+ ‐ROS/C/EBPβ axis, ultimately impairing their osteogenic capacity.