Int Immunopharmacol. 2026 May 27;184:116921. doi: 10.1016/j.intimp.2026.116921. Online ahead of print.
ABSTRACT
Atherosclerosis is a chronic inflammatory vascular disease characterized by lipid deposition, endothelial dysfunction, and cellular senescence, posing a significant threat to the cardiovascular system. As demonstrated in previous studies, phlorizin has been shown to have anti-atherosclerotic effects. However, the precise molecular mechanisms by which this occurs remain to be elucidated. This study aimed to investigate the preventive effect of phlorizin on atherosclerosis and elucidate the molecular network mediated by bone morphogenetic protein 10 (BMP10). A total of 40 eight-week-old Apoe-/- mice were randomly divided into four groups (n = 10): control, model, phlorizin, and phlorizin+sh-BMP10 groups. Following a 12-week period of observation, phlorizin was found to have a significant impact on lipid metabolism disorders, whilst concomitantly inhibiting the formation of aortic sinus plaque. Furthermore, phlorizin was found to inhibit vascular endothelial cell senescence and inflammatory responses, whilst concomitantly modulating oxidative stress levels in mice. Transcriptome sequencing revealed that after phlorizin intervention, differentially expressed genes (DEGs) in mouse aortic tissue were significantly enriched in cellular senescence, cell-cell adhesion, and p53 signaling pathways. Among the phlorizin-regulated DEGs involved in atherosclerosis and cellular senescence, BMP10 emerged as a target for further investigation. Dual-luciferase reporter assay confirmed that phlorizin upregulates BMP10 by activating its promoter at the transcriptional level. In vitro experiments confirmed that phlorizin upregulates BMP10 expression, alleviates oxidative LDL-induced cellular senescence and lipid deposition, and enhances cellular angiogenic capacity and migratory function. The anti-AS effect of phlorizin depends on the Smad5 signaling pathway downstream of BMP10. Endothelial-specific BMP10 knockdown verified that the protective effect was specifically mediated by vascular endothelial cells. The efficacy of this approach was further validated through the use of sh-AAV-BMP10, which successfully induced BMP10 knockdown in mice. The knockdown efficiency of BMP10 at mRNA and protein levels was verified in aortic tissue. In addition, the in vitro interference of BMP10 expression in vascular endothelial cells using si-BMP10 further corroborated the anti-atherosclerotic effects of phlorizin, thereby confirming that BMP10 deficiency was entirely sufficient to reverse these effects. The results of molecular docking indicated stable interactions between phlorizin and both human and mouse BMP10. Mechanistically, phlorizin transcriptionally activates BMP10 and functions through the BMP10-Smad5 signaling axis to inhibit endothelial senescence, inflammation, and oxidative stress.
PMID:42202394 | DOI:10.1016/j.intimp.2026.116921