SIRT6 transient silencing experiments denied the beneficial effects of iPCSK9 treatment, indicating that the pleiotropic functions of iPCSK9 may occur, at least in part, via modulation of SIRT6 and Forkhead box O3 (FOXO3A) expression levels.<h4>Conclusions</h4>Overall, the results indicate that PCSK9 inhibition via evolocumab exhibits substantial promise in the prevention of MP-induced endothelial dysfunction, suggesting the PCSK9-SIRT6 axis as a new promising pathway to target in preventive strategies for cardiovascular risk caused by plastic pollution. The gene discussed is SIRT6; the disease is endothelial dysfunction.