Naringenin inhibited vascular calcification and attenuated senescence-associated changes through the p53/TOP2Aaxis

Background Vascular calcification (VC) is a major cardiovascular complication of chronic kidney disease (CKD). Senescence-associated vascular changes have been increasingly implicated in CKD-related VC. Naringenin, a natural flavonoid with anti-oxidative and anti-inflammatory properties, has shown protective effects in several age-related disorders, but its role and mechanism in CKD-associated VC remain unclear. Methods Human vascular specimens, high-Pi-induced vascular smooth muscle cells (VSMCs), and an adenine/high-phosphate-induced rat model of CKD-associated VC were used to evaluate the relationship between calcification and senescence-associated changes and to assess the effects of naringenin. Histological staining, SA-β-Gal staining, Western blotting, immunofluorescence, immunohistochemistry, RNA sequencing, molecular docking, chromatin immunoprecipitation, and dual-luciferase assays were performed to explore the possible mechanism. Results VC was positively associated with senescence-associated changes in patient tissues, cultured VSMCs, and rat aortas. Naringenin significantly reduced calcium deposition and attenuated senescence-associated marker changes both in vitro and in vivo . Transcriptomic analysis implicated the p53 pathway and identified TOP2A as a downstream effector associated with naringenin treatment. Mechanistically, naringenin was associated with suppression of p53 signaling, relief of p53-mediated transcriptional repression of TOP2A, and restoration of TOP2A expression. Functional assays further suggested that p53 activation or TOP2A knockdown attenuated the protective effects of naringenin. Conclusion Naringenin inhibits vascular calcification by modulating the p53/TOP2A axis, and this protective effect is accompanied by attenuation of senescence-associated changes. These findings support naringenin as a mechanistically relevant candidate for CKD-associated vascular calcification, although the upstream mechanism underlying p53 suppression remains to be clarified.