Pseudoginsenoside F11 alleviates atherosclerosis by regulating SIRT3-mediated deacetylation of SOD2

Endothelial protection has emerged as a promising therapeutic strategy for cardiovascular diseases such as atherosclerosis (AS). However, no endothelial-targeted therapeutic drugs have yet been used in clinical practice. Pseudoginsenoside F11 (PF11), a characteristic saponin from Panax quinquefolius L., exerts cardiovascular protective effects, yet the mechanisms underlying its endothelial protective effects in AS remain unclear.

This study aimed to investigate the mechanisms by which PF11 protects vascular endothelium from injury and thereby ameliorates AS.

Mouse and zebrafish models were used to validate the ameliorative effect of PF11 on AS. Metabolomics, transcriptome sequencing (RNA-seq) and mitochondrial function assays were used to investigate the regulatory effect of PF11 on vascular endothelial cell injury. Pharmacological inhibition, gene silencing, and target-capture assays were used to elucidate the potential molecular mechanisms by which PF11 protects vascular endothelium.

PF11 significantly attenuated vascular injury in high-fat diet (HFD)-induced mouse and zebrafish models of AS, as indicated by reduced vessel wall thickening and decreased vascular lipid deposition. Moreover, PF11 markedly alleviated palmitic acid-induced endothelial cell dysfunction by reducing apoptosis and inflammatory responses, restoring NO production, and suppressing mitochondrial oxidative stress, thereby exerting vasoprotective effects. Mechanistically, PF11 directly bound to mitochondrial SIRT3 in endothelial cells. This interaction enhanced SIRT3-mediated deacetylation of the downstream protein SOD2, thereby counteracting the HFD-induced increase in intracellular ROS. Following pharmacological inhibition of SIRT3, PF11 restored mitochondrial ROS scavenging in endothelial cells, whereas SIRT3 knockdown attenuated its protective effects on endothelial injury.

This study demonstrated that PF11 exerted significant protective effects against AS. The protective effects of PF11 were closely associated with SIRT3 targeting, which preserved mitochondrial function and attenuated HFD-induced vascular endothelial injury. These findings suggest that PF11 may be a promising therapeutic candidate for endothelial injury and offer a novel endothelial-centered perspective for the treatment of AS.