Polydatin alleviates vascular calcification via the TP53/PI3K/AKT axis.

Vascular calcification (VC) is a major complication of chronic kidney disease (CKD), diabetes, atherosclerosis, and aging that significantly increases cardiovascular mortality, yet effective therapeutic interventions are currently limited. In this study, we demonstrated that Polydatin (PD), a natural polyphenolic compound, effectively alleviated VC across in vitro, ex vivo and in vivo models. PD treatment markedly reduced calcium deposition, decreased alkaline phosphatase (ALP) activity, and downregulated the expression of osteogenic markers (RUNX2 and BMP2). Network pharmacology analysis identified TP53 as a central candidate target. Molecular docking and cellular thermal shift assays (CETSA) confirmed a direct interaction between PD and P53 protein. Mechanistically, PD facilitated the degradation of P53 via the ubiquitin-proteasome pathway, thereby activating the PI3K/AKT signaling pathway. Notably, the anti-calcific effect of PD was abolished upon TP53 overexpression, confirming the indispensability of this regulatory pathway. Collectively, our findings establish PD as a potent inhibitor of VC and unveil the targeted modulation of the TP53-PI3K/AKT axis as a promising therapeutic strategy.