Targeting PTK2 by vaccarin alleviates osteoporosis through inhibiting ferroptosis via modulating P53 acetylation/succinylation.

Osteoporosis (OP) is a systemic skeletal disorder marked by reduced bone density and deterioration of trabecular microstructure. Recent studies have established ferroptosis as a major contributor to osteoporotic bone loss; however, the specific molecular mechanisms underlying this process remain incompletely understood. In this study, RNA sequencing revealed decreased expression of protein tyrosine kinase 2 (PTK2) in OP, while bioinformatics analyses identified a significant association between PTK2 and the ferroptosis-related gene P53. Mechanistically, lysine acetyltransferase 8 (MOF) acts as a key acetyltransferase for P53 acetylation. We found that PTK2 negatively regulates ferroptosis by competitively binding with MOF, thereby inhibiting both the acetylation and succinylation of P53 at the K120 site. This inhibition restores the transcriptional expression of fibronectin 1 (FN1). Using computer-aided molecular docking, we identified vaccarin-a bioactive small-molecule compound from the Selleck.cn natural product library-as a PTK2-targeting agent. Vaccarin not only suppressed erastin-induced ferroptosis but also enhanced the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Finally, we demonstrated that adenoviral overexpression of PTK2 (ADV-PTK2) or treatment with Vaccarin attenuated ovariectomy (OVX)-induced ferroptosis and osteoporosis in mice. These findings highlight PTK2 as a promising therapeutic target for OP and suggest that targeting PTK2-mediated ferroptosis inhibition may offer a novel therapeutic approach for osteoporosis management.