Bisphenol A exacerbates osteoblast ferroptosis via the p53/SLC7A11 axis: A novel mechanistic insight into environmental osteoporosis pathogenesis.

Bisphenol A (BPA) is a ubiquitous industrial pollutant, but its role in osteoporosis is not fully understood. This paper combines network toxicology, experimental, and molecular docking validation to illuminate how BPA disrupts bone metabolism. We identified 142 BPA related proteins linked to osteoporosis, narrowing to 6 core targets by protein-protein interaction analysis. Molecular docking confirmed strong binding of BPA to these targets. In vitro and in vivo experiments showed that BPA suppressed osteoblast viability and differentiation. Quantitative analyses further revealed strong negative correlations between BPA exposure levels on key osteogenic parameters, such as reduced alkaline phosphatase activity, downregulation of OPN, OCN, and RUNX2. Mechanically, BPA induces osteoblastic ferroptosis by increasing the accumulation of p53, which enhances degradation of SLC7A11, which is a critical ferroptosis protein. Notably, we show a novel post-translational regulatory mechanism where p53 regulates SLC7A11 protein stability, rather than transcription. We show a novel toxicological mechanism by which BPA exacerbates osteoporosis and provide a new target for potential therapeutic interventions focused on protein stability and post-translational modifications.